5-Heteroatom-substituted pyrazoles

ABSTRACT

The present invention relates to 5-heteroatom-substituted pyrazoles of the formula I:  
                 
 
     wherein the ring of the formula (R 5 )-A-(SO m R 4 ), m, B, R 1  through R 5  are as defined in the specification, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the invention are useful in the treatment or alleviation of inflammation and other inflammation associated disorders, such as arthritis, colon cancer, and Alzheimer&#39;s disease in mammals, preferably humans, dogs, cats and livestock animals.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims benefit of U.S. provisional applicationNo. 60/335,733, filed Nov. 2, 2001.

BACKGROUND OF THE INVENTION

[0002] This invention relates to 5-heteroatom-substituted pyrazoles,methods of treatment and pharmaceutical compositions for the treatmentof cyclooxygenase mediated diseases, such as arthritis,neurodegeneration and colon cancer, in mammals, preferably humans, dogs,cats or livestock.

[0003] Sulfonyl pyrazoles are useful in the treatment of cyclooxygenase(COX) mediated diseases, such as arthritis, neurodegeneration and coloncancer, in mammals, preferably humans, dogs, cats or livestock. Twoforms of COX are now known, a constitutive isoform (COX-1) and aninducible isoform (COX-2) of which expression is upregulated at sites ofinflammation (Vane, J. R.; Mitchell, et. al., Proc. Natl. Acad. Sci.USA, 1994, 91, 2046). COX-1 appears to play a physiological role and tobe responsible for gastrointestinal and renal protection. On the otherhand, COX-2 appears to play a pathological role and is believed to bethe predominant isoform present in inflammation conditions. Thetherapeutic use of conventional COX inhibitors are limited due to drugassociated side effects, including life threatening ulceration and renaltoxicity. Compounds that selectively inhibit COX-2 would exertanti-inflammatory effects without the adverse side effects associatedwith COX-1 inhibition. Preferred compounds of the invention areselective COX-2 inhibitors.

[0004] A variety of sulfonylpyrazoles that inhibit COX have beendescribed in patent publications WO 97/11704, WO 01/40216, EP 1104758,EP 1104759, and EP 1104760; U.S. Non-Provisional patent application Ser.No. 09/798,752, filed Mar. 2, 2001; and U.S. Non-Provisional patentapplication Ser. No. 09/824,550, filed Apr. 2, 2001.

[0005] Filed simultaneously with the present application on Nov. 2,2001, are United States Provisional Applications entitled “Hydrazinyland Nitrogen Oxide Pyrazoles”; “Heterocyclo-Alkylsulfonyl Pyrazoles”;“5-Heterocyclo-Pyrazoles”; and “5-(Alkylidene-Cycloalkyl)- and5-(Alkylidene-Heterocyclyl)-Pyrazoles”, which refer to certain pyrazoleCOX-2 inhibitors. The aforesaid applications are herein incorporated intheir entireties by reference.

SUMMARY OF THE INVENTION

[0006] The present invention relates to a compound of the formula I:

[0007] or the pharmaceutically acceptable salts thereof;

[0008] wherein the ring of the formula (R⁵)-A-(SO_(m)R⁴) is selectedfrom the group consisting of

[0009] m is 0, 1 or 2;

[0010] X is >CR⁵ or >N;

[0011] R¹ is a radical selected from the group consisting of H, —NO₂,—CN, (C₁-C₆)alkyl, (C₁-C₆)alkyl-SO₂—, (C₆-C₁₀)aryl-SO₂—, H—(C═O)—,(C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, (C₁-C₉)heteroaryl-(C═O)—,(C₁-C₉)heterocyclyl-(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂-NH—(C═O)—, [(C₆-C₁₀)aryl]-NH—(C═O)—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—(C═O)—, HO—NH—(C═O)—, or(C₁-C₆)alkyl-O—NH—(C═O)—;

[0012] R² is a radical selected from the group consisting of H, —NO₂,—CN, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, (C₆-C₁₀)aryl,(C₁-C₉)heteroaryl, (C₁-C₉)heterocyclyl, (C₁-C₆)alkyl-O—,(C₃-C₇)cycloalkyl-O—, (C₆-C₁₀)aryl-O—, (C₁-C₉)heteroaryl-O—,(C₁-C₉)heterocyclyl-O—, H—(C═O)—, (C₁-C₆)alkyl-(C═O)—,(C₃-C₇)cycloalkyl-(C═O)—, (C₆-C₁₀)aryl-(C═O)—, (C₁-C₉)heteroaryl-(C═O)—,(C₁-C₉)heterocyclyl-(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₇)cycloalkyl-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclyl-O—(C═O)—,(C₁-C₆)alkyl-(C═O)—O—, (C₃-C₇)cycloalkyl-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₇)cycloalkyl-(C═O)—NH—, (C₆-C₁₀)aryl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclyl-(C═O)—NH—,(C₁-C₆)alkyl-O—(C═O)—NH—, (C₁-C₆)alkyl-NH—, [(C₁-C₆)alkyl]₂-N—,(C₃-C₇)cycloalkyl-NH—, [(C₃-C₇)cycloalkyl]₂-N—, [(C₆-C₁₀)aryl]-NH—,[(C₆-C₁₀)aryl]₂-N—, [(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—,[(C₁-C₉)heteroaryl]-NH—, [(C₁-C₉)heteroaryl]₂-N—,[(C₁-C₉)heterocyclyl]-NH—, [(C₁-C₉)heterocyclyl]₂-N—, H₂N—(C═O)—,HO—NH—(C═O)—, (C₁-C₆)alkyl-O—NH—(C═O)—, [(C₁-C₆)alkyl]-NH—(C═O)—,[(C₁-C₆)alkyl]₂-NH—(C═O)—, [(C₃-C₇)cycloalkyl]-NH—(C═O)—,[(C₃-C₇)cycloalkyl]₂-NH—(C═O)—, [(C₆-C₁₀)aryl]-NH—(C═O)—,[(C₆-C₁₀)aryl]₂-NH—(C═O)—, [(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—(C═O)—,[(C₁-C₉)heteroaryl]-NH—(C═O)—, [(C₁-C₉)heteroaryl]₂-NH—(C═O)—,[(C₁-C₉)heterocyclyl]-NH—(C═O)—, (C₁-C₆)alkyl-S—, and (C₁-C₆)alkyloptionally substituted by one —OH substituent or by one to four fluorosubstituents;

[0013] B is —O—, —S—, —SO—, —SO₂— or R⁶—N—;

[0014] R³ is a radical selected from the group consisting of(C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, (C₁-C₉)heteroaryl and(C₁-C₉)heterocyclyl;

[0015] wherein each of said R³ (C₁-C₆)alkyl, (C₆-C₁₀)aryl,(C₃-C₁₀)cycloalkyl, (C₁-C₉)heteroaryl or (C₁-C₉)heterocyclyl radicalsmay optionally be substituted with one to three substituentsindependently selected from the group consisting of halo, —NH₂, —OH,—CN, —NO₂, —OCF₃, —CF₃, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, (C₁-C₉)heteroaryl,(C₁-C₉)heterocyclyl, (C₁-C₆)alkyl-O—, (C₃-C₁₀)cycloalkyl-O—,(C₆-C₁₀)aryl-O—, (C₁-C₉)heteroaryl-O—, and (C₁-C₉)heterocyclyl-O—;

[0016] wherein each of said R³ (C₁-C₆)alkyl, (C₆-C₁₀)aryl,(C₃-C₁₀)cycloalkyl, (C₁-C₉)heterocyclyl or (C₁-C₉)heteroarylsubstituents may optionally be substituted with one to three moietiesindependently selected from the group consisting of halo, —NH₂, HO—,(C₁-C₆)alkyl-O—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl-CN, —NO₂,—OCF₃, and —CF₃;

[0017] wherein each of said —NH₂ substituents may optionally besubstituted by one to two moieties independently selected from the groupconsisting of (C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl,(C₁-C₉)heterocyclyl and (C₁-C₉)heteroaryl, wherein said moieties areoptionally substituted by one or two sub-moieties independently selectedfrom the group consisting of halo, —NH₂, HO—, (C₁-C₆)alkyl-O—,(C₁-C₆)alkyl, —OCF₃ and —CF₃;

[0018] R⁴ is a radical selected from the group consisting of(C₁-C₆)alkyl-NH—, [(C₁-C₆)alkyl]₂-N—, (C₃-C₇)cycloalkyl-NH—,(C₆-C₁₀)aryl-NH—, (C₁-C₉)heteroaryl-NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₇)cycloalkyl-(C═O)—NH—, (C₆-C₁₀)aryl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₆)alkyl-O—(C═O)—NH—,(C₃-C₇)cycloalkyl-O—(C═O)—NH—, (C₆-C₁₀)aryl-O—(C═O)—NH—,(C₁-C₉)heteroaryl-O—(C═O)—NH—, (C₁-C₆)alkyl-NH—(C═O)—NH—,[(C₁-C₆)alkyl]₂-NH—(C═O)—NH—, (C₃-C₇)cycloalkyl-NH—(C═O)—NH—,(C₆-C₁₀)aryl-NH—(C═O)—NH—, (C₁-C₉)heteaoaryl]-NH—(C═O)—NH—,(C₁-C₆)alkyl-NH—HC═N—, (C₁-C₆)alkyl]₂N—HC═N—, and (C₆-C₁₀)aryl-NH—HC═N—;

[0019] R⁵ is a radical selected from the group consisting of H, halo,—OH, (C₁-C₆)alkyl-O—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl,—CN, H—(C═O)—, (C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkyl-(C═O)—O—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, (C₁-C₆)alkyl-NH—, [(C₁-C₆)alkyl]₂-N—,(C₃-C₇)cycloalkyl-NH—, (C₆-C₁₀)aryl-NH—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—, (C₁-C₉)heteroaryl-NH—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂-NH—(C═O)—, (C₆-C₁₀)aryl-(C═O)—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—(C═O)—,(C₁-C₆)alkyl-O—NH—(C═O)—,(C₁-C₆)alkyl-S—, and (C₁-C₆)alkyl optionally substituted with one tofour fluoro atoms; and

[0020] R⁶ is a radical selected from the group consisting of H,(C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, (C₁-C₉)heteroaryl and(C₁-C₉)heterocyclyl.

[0021] The present invention also relates to the pharmaceuticallyacceptable acid addition salts of compounds of the formula I. The acidswhich are used to prepare the pharmaceutically acceptable acid additionsalts of the aforementioned base compounds of this invention are thosewhich form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,para-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

[0022] The invention also relates to base addition salts of formula I.The chemical bases that may be used as reagents to preparepharmaceutically acceptable base salts of those compounds of formula Ithat are acidic in nature are those that form non-toxic base salts withsuch compounds. Such non-toxic base salts include, but are not limitedto those derived from such pharmacologically acceptable cations such asalkali metal cations (e.g., potassium and sodium) and alkaline earthmetal cations (e.g., calcium and magnesium), ammonium or water-solubleamine addition salts such as N-methylglucamine (meglumine), and thelower alkanolammonium and other base salts of pharmaceuticallyacceptable organic amines.

[0023] The compounds of this invention include all stereoisomers (e.g.,cis and trans isomers) and all optical isomers of compounds of theformula I (e.g., R and S enantiomers), as well as racemic,diastereomeric and other mixtures of such isomers.

[0024] The compounds of the invention also exist in different tautomericforms. This invention relates to all tautomers of formula I.

[0025] The compounds of this invention may contain olefin-like doublebonds. When such bonds are present, the compounds of the invention existas cis and trans configurations and as mixtures thereof.

[0026] The compounds of this invention may contain olefin-like doublebonds. When such bonds are present, the compounds of the invention existas cis and trans configurations and as mixtures thereof. Unlessotherwise indicated, the term “functional group” refers to “radical”,“substituent” “moiety”, or “sub-moiety”, as defined below. The term“sub-functional group” refers to “substituent” “moiety”, or“sub-moiety”, as defined below.

[0027] Unless otherwise indicated, the term “radical” or “radicals”refers to an individual member of a variable (R¹, R², R³ etc) of thecompound of the formula I (e.g., R¹ is a radical selected from the groupconsisting of H and (C₁-C₆)alkyl means that R¹ can be either a H radicalor a (C₁-C₆)alkyl radical).

[0028] Unless otherwise indicated, the term “substituent” or“substituents” refers to a replacement of at least one atom of aradical, wherein the term “radical” is as defined above, by another atomor group of atoms. For example, an (C₁-C₆)alkyl substituent may replacea hydrogen atom of R¹ (C₆-C₁₀)aryl radical.

[0029] Unless otherwise indicated, the term “moiety” or “moieties”refers to a replacement of at least one atom of a substituent, whereinthe term “substituent” is as defined above, by another atom or group ofatoms. For example, an (C₁-C₆)alkyl moiety of a particular substituent(e.g., (C₁-C₆)alkyl, (C₆-C₁₀)aryl, or (C₃-C₈)cycloalkyl substituent) mayreplace a hydrogen atom of that substituent.

[0030] Unless otherwise indicated, the term “sub-moiety” or“sub-moieties” refers to a replacement of at least one atom of a moiety,wherein the term “moiety” is as defined above, by another atom or groupof atoms. For example, an (C₁-C₆)alkyl sub-moiety of a particular moiety(e.g., (C₁-C₆)alkyl, (C₆-C₁₀)aryl, or (C₃-C₈)cycloalkyl moiety) mayreplace a hydrogen atom of that moiety.

[0031] Unless otherwise indicated, the term “(C₁-C₆)alkyl” as well asthe (C₁-C₆)alkyl component of other terms referred to herein (e.g., the“(C₁-C₆)alkyl component of (C₁-C₆)alkyl-O—), may be linear or branched(such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,secondary-butyl, tertiary-butyl), wherein each of said (C₁-C₆)alkylfunctional group, wherever they occur, may optionally be substituted byone to three sub-functional groups per (C₁-C₆)alkyl componentindependently selected from the group consisting of fluoro, —OH,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, (C₁-C₆)alkyl-O—, oxo,H—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-(C═O)—, —CN, —NO₂,(C₁-C₆)alkyl-O—(C═O)—, (C₁-C₆)alkyl-NH—, [(C₁-C₆)alkyl]₂-N—,(C₃-C₇)cycloalkyl-NH—, (C₆-C₁₀)aryl-NH—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—, (C₁-C₉)heteroaryl-NH—,(C₁-C₁₀)heterocyclyl-NH—, H₂N—(C═O)—, [(C₁-C₆)alkyl]-NH—(C═O)—,[(C₁-C₆)alkyl]₂-N—(C═O)—, [(C₆-C₁₀)aryl]-NH—(C═O)—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—(C═O)—, (C₁-C₆)alkyl-O—NH—(C═O)—,(C₆-C₁₀)aryl, (C₂-C₉)heteroaryl, (C₆-C₁₀)aryl-O—, (C₁-C₉)heteroaryl-O—,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—(C₁-C₆)alkyl-NH and (C₁-C₆)alkyl-(C═O)—O—.

[0032] Unless otherwise indicated, the term “halo” means fluoro, chloro,bromo or iodo.

[0033] Unless otherwise indicated, the term “(C₂-C₆)alkenyl” meansstraight or branched hydrocarbon chain functional groups of 2 to 6carbon atoms having at least one double bond including, but not limitedto ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, or 2-butenyl.

[0034] Unless otherwise indicated, the term “(C₂-C₆)alkynyl” is usedherein to mean straight or branched hydrocarbon chain functional groupsof 2 to 6 carbon atoms having one triple bond including, but not limitedto, ethynyl (—C≡C—H), propynyl (—CH₂—C≡C—H or —C≡C—CH₃), or butynyl(—CH₂—CH₂—C≡C—H, or —CH₂—C≡C—CH₃, or —C≡C—CH₂CH₃).

[0035] Unless otherwisse indicated, the term “(C₃-C₇)cycloalkyl” refersto a mono or bicyclic carbocyclic ring functional groups including, butnot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, bicyclo[2.2.1]heptanyl,bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl; wherein said(C₃-C₇)cycloalkyl may optionally contain 1 or 2 double bonds including,but not limited to, cyclopentenyl, cyclohexenyl and cycloheptenyl.

[0036] Unless otherwise indicated, the term “(C₆-C₁₀)aryl” meansaromatic functional groups such as phenyl, naphthyl, tetrahydronaphthyl,or indanyl, wherein said (C₆-C₁₀)aryl is optionally substituted on anyring carbon atom by one to two sub-functional groups per ring, whereinsaid sub-functional groups are independently selected from the groupconsisting of halo, —OH, —CN, —SH, HO—(C═O)—, —NO₂, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, (C₆-C₁₀)aryl,(C₁-C₉)heteroaryl, (C₁-C₉)heterocyclyl, (C₁-C₆)alkyl-O—, —OCF₃,(C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-NH—, [(C₁-C₆)alkyl]₂-N—,(C₃-C₇)cycloalkyl-NH—, (C₆-C₁₀)aryl-NH—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—, (C₁-C₉)heteroaryl-NH—,(C₁-C₁₀)heterocyclyl-NH—, H₂N—(C═O)—, [(C₁-C₆)alkyl]-NH—(C═O)—,[(C₁-C₆)alkyl]₂-N—(C═O)—, [(C₆-C₁₀)aryl]-NH—(C═O)—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—(C═O)—, (C₁-C₆)alkyl-O—NH—(C═O)—,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—NH—(C₁-C₆)alkyl-(C═O)—HN—(C₁-C₆)alkyl-NH, H—(C═O)—, (C₁-C₆)alkyl-(C═O)— and(C₁-C₆)alkyl-O—(C═O)—.

[0037] Unless otherwise indicated, the term“[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—” has the following structure:

[0038] wherein the term “(C₁-C₆)alkyl” and the term “(C₆-C₁₀)aryl” areas defined above.

[0039] Unless otherwise indicated, the term“[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—(C═O)—” has the following structure:

[0040] wherein the term “(C₁-C₆)alkyl” and the term “(C₆-C₁₀)aryl” areas defined above.

[0041] Unless otherwise indicated, the term “oxo” refers to ═O.

[0042] Unless otherwise indicated, the term “[(C₁-C₆)alkyl]-NH—HC═N—”refers to

[0043] wherein the term “(C₁-C₆)alkyl” is as defined above.

[0044] Unless otherwise indicated, the term “[C₁-C₆)alkyl]₂N—HC═N—”refers to

[0045] wherein the term “(C₁-C₆)alkyl” is as defined above.

[0046] Unless otherwise indicated, the term “[(C₆-C₁₀)aryl]-NH—HC═N—”refers to

[0047] wherein the term “(C₆-C₁₀)aryl” is as defined above.

[0048] Unless otherwise indicated, the term “(C₁-C₉)heteroaryl” refersto aromatic or multicyclic functional groups wherein at least one ringof the functional groups is aromatic, wherein said aromatic ormulticyclic functional groups contain one or more heteroatoms selectedfrom the group consisting of O, S and N. The (C₁-C₉)heteroarylfunctional groups can also be optionally substituted by one or more oxosub-functional groups. Examples of heteroaryl functional groups include,but are not limited to, benzimidazolyl, benzofuranyl, benzofurazanyl,2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl,benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl,furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl,indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl,pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl,pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl,thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said(C₁-C₁₀)heteroaryl is optionally substituted on any atoms capable offorming an additional bond by one or two sub-functional groupsindependently selected from halo, —CN, —OH, (C₁-C₆)alkyl,perfluoro(C₁-C₆)alkyl, perfluoro(C₁-C₆)alkyl-O—, (C₁-C₆)alkyl-O— and(C₃-C₈)cycloalkyl-O—. Unless otherwise indicated, the foregoing(C₁-C₉)heteroaryls functional groups can be C-attached or N-attachedwhere such is possible. For instance, pyrrolyl can be pyrrol-1-yl(N-attached) or pyrrol-3-yl (C-attached).

[0049] Unless otherwise indicated, the term “(C₁-C₉)heterocyclyl” refersto a cyclic functional groups containing 1 to 9 carbon atoms and 1 to 4heteroatoms selected from the group consisting of N, O and S. Theheterocyclyl ring functional groups can also be optionally substitutedwhere such is possible by oxo, —CN, —OH, (C₁-C₆)alkyl,perfluoro(C₁-C₆)alkyl, perfluoro(C₁-C₆)alkyl-O—, (C₁-C₆)alkyl-O— and(C₃-C₈)cycloalkyl-O—. Examples of the cyclic functional groups include,but not limited to, 3-azabicyclo[3.1.0]hexanyl,3-azabicyclo[4.1.0]-heptanyl, azetidinyl, dihydrofuranyl,dihydropyranyl, dihydrothienyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl,hexahydroazepinyl, hexahydropyrimidine, imidazolidinyl, imidazolinyl,isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl,2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl,2-pyrrolinyl, 3-pyrrolinyl, quinolizinyl, tetrahydrofuranyl,tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothienyl,tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl or trithianyl. Unlessotherwise indicated, the foregoing heterocyclyl can be C-attached orN-attached where such is possible. For example, piperidinyl can bepiperidin-1-yl (N-attached) or piperidin-4-yl (C-attached).

[0050] In one embodiment of the invention, R⁴ is a radical selected fromthe group consisting of (C₁-C₆)alkyl-NH—, [(C₁-C₆)alkyl]₂-N—,(C₃-C₇)cycloalkyl-NH—, (C₆-C₁₀)aryl-NH—, (C₁-C₉)heteroaryl-NH—;preferably selected from the group consisting of (C₁-C₆)alkyl-NH— and(C₃-C₇)cycloalkyl-NH—; more preferably selected from the groupconsisting of methyl-NH—, ethyl-NH, cyclopropyl-NH—, cyclopentyl-NH—,and cyclohexyl-NH—.

[0051] In another embodiment of the invention, R⁴ is a radical selectedfrom the group consisting of (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₇)cycloalkyl-(C═O)—NH—, (C₆-C₁₀)aryl-(C═O)—NH—, and(C₁-C₉)heteroaryl-(C═O)—NH—; preferably selected from the groupconsisting of (C₁-C₆)alkyl-(C═O)—NH— and (C₆-C₁₀)aryl-(C═O)—NH—;preferably phenyl-(C═O)—NH—.

[0052] In another embodiment of the invention, R⁴ is a radical selectedfrom the group consisting of (C₁-C₆)alkyl-O—(C═O)—NH—,(C₃-C₇)cycloalkyl-O—(C═O)—NH—, (C₆-C₁₀)aryl-O—(C═O)—NH—, and(C₁-C₉)heteroaryl-O—(C═O)—NH—; preferably selected from the groupconsisting of (C₁-C₆)alkyl-O—(C═O)—NH— and (C₆-C₁₀)aryl-O—(C═O)—NH—;more preferably methyl-O—(C═O)—NH—.

[0053] In another embodiment of the invention, R⁴ is a radical selectedfrom the group consisting of (C₁-C₆)alkyl-NH—(C═O)—NH—,[(C₁-C₆)alkyl]₂-NH—(C═O)—NH—, (C₃-C₇)cycloalkyl-NH—(C═O)—NH—,(C₆-C₁₀)aryl-NH—(C═O)—NH—, and (C₁-C₉)heteroaryl]-NH—(C═O)—NH—;preferably selected from the group consisting of[(C₁-C₆)alkyl]-NH—(C═O)—NH—, [(C₁-C₆)alkyl]₂-NH—(C═O)—NH—, and[(C₆-C₁₀)aryl]-NH—(C═O)—NH—.

[0054] In another embodiment of the invention, R⁴ is a radical selectedfrom the group consisting of (C₁-C₆)alkyl-NH—HC═N—,[C₁-C₆)alkyl]₂N—HC═N—, and (C₆-C₁₀)aryl-NH—HC═N—; preferably selectedfrom the group consisting of [(C₁-C₆)alkyl]-NH—HC═N—,[C₁-C₆)alkyl]₂N—HC═N—, and [(C₆-C₁₀)aryl]-NH—HC═N—.

[0055] In another embodiment of the invention, R⁴ is a radical selectedfrom the group consisting of (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-O—(C═O)—NH—, (C₁-C₆)alkyl-NH—, and [(C₁-C₆)alkyl]-NH—HC═N—;preferably selected from the group consisting of methyl-(C═O)—NH—,ethyl-(C═O)—NH—, sec-butyl-(C═O)—NH—, isobutyl-(C═O)—NH—,tert-butyl-(C═O)—NH—, methyl-O—(C═O)—NH—, ethyl-O—(C═O)—NH—,sec-butyl-O—(C═O)—NH—, isobutyl-O—(C═O)—NH—, tert-butyl-O—(C═O)—NH—,methyl-NH—, ethyl-NH—, sec-butyl-NH—, isobutyl-NH—, tert-butyl-NH—,methyl-NH—HC═N—, and ethyl-NH—HC═N—.

[0056] In another embodiment of the invention, B is —O—.

[0057] In another embodiment of the invention, B is —S—, —SO—, or —SO₂—.

[0058] In another embodiment of the invention, B is —SO₂—.

[0059] In another embodiment of the invention, B is R⁶—N—; wherein R⁶ ispreferably H or methyl.

[0060] In another embodiment of the invention, R³ is a radical selectedfrom the group consisting of (C₁-C₆)alkyl; (C₃-C₁₀)cycloalkyl, and(C₁-C₉)heterocyclyl.

[0061] In another embodiment of the invention, R³ is an (C₁-C₆)alkylradical; preferably selected from the group consisting of methyl, ethyl,sec-butyl, isobutyl, and tert-butyl.

[0062] In another embodiment of the invention, R³ is a(C₃-C₁₀)cycloalkyl radical; preferably selected from the groupconsisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0063] In another embodiment of the invention, R³ is a(CG-C₉)heterocyclyl radical; preferably selected from the groupconsisting of tetrahydrofuran-1-yl and tetrahydropyran-1-yl.

[0064] In another embodiment of any of the foregoing embodiments of theinvention, the ring of the formula (R⁵)-A-(SO_(m)R⁴) is of the formula

[0065] preferably A2; wherein X is >CR⁵; wherein R⁵ is preferably H, andm is 0, 1 or 2, preferably m is 2.

[0066] In another embodiment of any of the foregoing embodiments of theinvention, the ring of the formula (R⁵)-A-(SO_(m)R⁴) is of the formula

[0067] wherein m is 0, 1 or 2, preferably m is 2.

[0068] In another embodiment of any of the foregoing embodiments of theinvention, the ring of the formula (R⁵)-A-(SO_(m)R⁴) is of the formula

[0069] In another embodiment of any of the foregoing embodiments of theinvention, R¹ is a radical selected from the group consisting of —NO₂,—CN, (C₁-C₆)alkyl, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, and [(C₁-C₆)alkyl]₂-NH—(C═O).

[0070] In another embodiment of any of the foregoing embodiments of theinvention, R¹ is a radical selected from the group consisting of H,—NO₂, and —CN; preferably R¹ is —CN.

[0071] In another embodiment of any of the foregoing embodiments of theinvention, R¹ is a radical selected from the group consisting ofH—(C═O)—, (C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₁-C₉)heteroaryl-(C═O)—, and (C₁-C₉)heterocyclyl-(C═O)—.

[0072] In another embodiment of any of the foregoing embodiments of theinvention, R¹ is a radical selected from the group consisting ofH₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂-N—(C═O)—,[(C₆-C₁₀)aryl]-NH—(C═O)—, [(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—(C═O)—,HO—NH—(C═O)—, and (C₁-C₆)alkyl-O—NH—(C═O)—.

[0073] In another preferred embodiment of any of the foregoingembodiments of the invention, R² is a radical selected from the groupconsisting of H, —NO₂, —CN, or (C₁-C₆)alkyl optionally substituted byone —OH substituent or by one to four fluoro substituents; preferably R²is an (C₁-C₆)alkyl radical optionally substituted by one —OH substituentor by one to four fluoro substituents; more preferably R² is —CF₃ or—CHF₂.

[0074] In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, (C₆-C₁₀)aryl,(C₁-C₉)heteroaryl, and (C₁-C₉)heterocyclyl.

[0075] In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of(C₁-C₆)alkyl-O—, (C₃-C₇)cycloalkyl-O—, (C₆-C₁₀)aryl-O—,(C₁-C₉)heteroaryl-O—, and (C₁-C₉)heterocyclyl-O—.

[0076] In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting ofH—(C═O)—, (C₁-C₆)alkyl-(C═O)—, (C₃-C₇)cycloalkyl-(C═O)—,(C₆-C₁₀)aryl-(C═O)—, (C₁-C₉)heteroaryl-(C═O)—, and(C₁-C₉)heterocyclyl-(C═O)—.

[0077] In another embodiment of any of the foregoing embodiments of theinvention, R¹ is a radical selected from the group consisting of(C₁-C₆)alkyl-O—(C═O)—, (C₃-C₇)cycloalkyl-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)— and(C₁-C₉)heterocyclyl-O—(C═O)—.

[0078] In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of(C₁-C₆)alkyl-(C═O)—O—, (C₃-C₇)cycloalkyl-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—, and(C₁-C₉)heterocyclyl-(C═O)—O—.

[0079] In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₇)cycloalkyl-(C═O)—NH—,(C₆-C₁₀)aryl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclyl-(C═O)—NH—, and (C₁-C₆)alkyl-O—(C═O)—NH—.

[0080] In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of(C₁-C₆)alkyl-NH—, [(C₁-C₆)alkyl]₂-N—, (C₃-C₇)cycloalkyl-NH—,[(C₃-C₇)cycloalkyl]₂-N—, [(C₆-C₁₀)aryl]-NH—, [(C₆-C₁₀)aryl]₂-N—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—, [(C₁-C₉)heteroaryl]-NH—,[(C₁-C₉)heteroaryl]₂-N—, [(C₁-C₉)heterocyclyl]-NH—, and[(C₁-C₉)heterocyclyl]₂-N—.

[0081] In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting ofH₂N—(C═O)—, HO—NH—(C═O)—, and (C₁-C₆)alkyl-O—NH—(C═O)—.

[0082] In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of[(C₁-C₆)alkyl]-NH—(C═O)—, [(C₁-C₆)alkyl]₂-N—(C═O)—,[(C₃-C₇)cycloalkyl]-NH—(C═O)—, [(C₃-C₇)cycloalkyl]₂-N—(C═O)—,[(C₆-C₁₀)aryl]-NH—(C═O)—, [(C₆-C₁₀)aryl]₂-N—(C═O)—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—(C═O)—, [(C₁-C₉)heteroaryl]-NH—(C═O)—,[(C₁-C₉)heteroaryl]₂-N—(C═O)—, [(C₁-C₉)heterocyclyl]-NH—(C═O)—, and(C₁-C₆)alkyl-S—.

[0083] In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is H halo or —CN.

[0084] In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is —OH or (C₁-C₆)alkyl-O—.

[0085] In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is (C₂-C₆)alkenyl or (C₂-C₆)alkynyl.

[0086] In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is (C₃-C₇)cycloalkyl.

[0087] In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is H—(C═O)—, (C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkyl-(C═O)—O—,HO—(C═O)—, or (C₁-C₆)alkyl-O—(C═O)—.

[0088] In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is (C₁-C₆)alkyl-NH—, [(C₁-C₆)alkyl]₂-N—,(C₃-C₇)cycloalkyl-NH—, (C₆-C₁₀)aryl-NH—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—, or (C₁-C₉)heteroaryl-NH—.

[0089] In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₈)alkyl]₂-N—(C═O)—, (C₆-C₁₀)aryl-(C═O)—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—(C═O)—, or (C₁-C₆)alkyl-O—NH—(C═O)—.

[0090] In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is (C₁-C₆)alkyl-S—.

[0091] In a preferred embodiment of the present invention, R⁵ is H.

[0092] In another embodiment of the invention, R⁶ is H.

[0093] In another embodiment of the invention, R⁶ is (C₁-C₆)alkyl,preferably methyl.

[0094] In another embodiment of the invention, R⁶ is a radical selectedfrom the group consisting of (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl,(C₁-C₉)heteroaryl and (C₀-C₉)heterocyclyl.

[0095] In a preferred embodiment of the invention, R⁴ is a radicalselected from the group consisting of methyl-NH—, ethyl-NH,cyclopropyl-CH₂—NH—, cyclopentyl-NH—, cyclohexyl-NH—, methyl-NH—HC═N—,and [methyl]₂N—HC═N—; B is —O—, —N— or —SO₂—; R³ is a radical selectedfrom the group consisting of sec-butyl, isobutyl, tert-butyl, —CH₂—(cyclobutyl), and —CH₂— (tetrahydrofuran-2-yl); the ring of the formula(R⁵)-A-(SO_(m)R⁴) is of the formula

[0096] more preferably A2; wherein X is >CH and m is 2; R¹ is —CN; R² isa radical selected from the group consisting of —CF₃ and —CHF₂; and R⁵is H.

[0097] Specific preferred compounds of formula I are selected from thegroup consisting of:

[0098]6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid acetyl-amide;

[0099]6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid propionyl-amide;

[0100]6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid isobutyryl-amide;

[0101]6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid (2,2-dimethyl-propionyl)-amide;

[0102]6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid (1,1-dimethyl)-ethoxy-amide;

[0103]6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid (3-methyl-butyryl)-amide;

[0104]6-(4-Cyano-5-cyclopentylmethoxy-3-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonic acid acetyl amide;

[0105]6-(4-Cyano-5-cyclopentylmethoxy-3-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonic acid propionyl amide;

[0106]6-(4-Cyano-5-cyclopentylmethoxy-3-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonic acid isobutyryl amide;

[0107]6-[4-Cyano-5-(2,2-dimethyl-propoxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid (1,1-dimethylethoxy)amide;

[0108]6-[4-Cyano-5-(2,2-dimethyl-propoxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid (3-methyl-butyryl) amide;

[0109]6-[4-Cyano-5-(2,2-dimethyl-propoxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid acetyl amide;

[0110]6-[4-Cyano-5-(3-methyl-cyclohexyloxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid propionyl amide;

[0111]6-[4-Cyano-5-(3-methyl-cyclohexyloxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid isobutyryl amide;

[0112]6-[4-Cyano-5-(3-methyl-cyclohexyloxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid (1,1-dimethylethoxy) amide;

[0113]6-(5-sec-Butylsulfanyl-4-cyano-3-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonicacid acetyl amide;

[0114]6-(5-sec-Butylsulfanyl-4-cyano-3-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonic acid (3-methyl-butyryl)amide;

[0115]6-(5-sec-Butylsulfanyl-4-cyano-3-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonicacid (1,1-dimethylethoxy)amide;

[0116]6-(5-sec-Butylsulfanyl-4-cyano-3-difluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonic acid acetyl amide;

[0117]6-(5-sec-Butylsulfanyl-4-cyano-3-difluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonicacid propionyl amide; and

[0118]6-(5-sec-Butylsulfanyl-4-cyano-3-difluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonic acid isobutyryl amide; or

[0119] the pharmaceutically acceptable salts thereof.

[0120] The present invention also relates to a pharmaceuticalcomposition for the treatment of a condition selected from the groupconsisting of arthritis (including osteoarthritis, degenerative jointdisease, spondyloarthropathies, gouty arthritis, systemic lupuserythematosus, juvenile arthritis and rheumatoid arthritis), fever(including rheumatic fever and fever associated with influenza and otherviral infections), common cold, dysmenorrhea, menstrual cramps,inflammatory bowel disease, Crohn's disease, emphysema, acuterespiratory distress syndrome, asthma, bronchitis, chronic obstructivepulmonary disease, Alzheimer's disease, organ transplant toxicity,cachexia, allergic reactions, allergic contact hypersensitivity, cancer(such as solid tumor cancer including colon cancer, breast cancer, lungcancer and prostrate cancer; hematopoietic malignancies includingleukemias and lymphomas; Hodgkin's disease; aplastic anemia, skin cancerand familiar adenomatous polyposis), tissue ulceration, peptic ulcers,gastritis, regional enteritis, ulcerative colitis, diverticulitis,recurrent gastrointestinal lesion, gastrointestinal bleeding,coagulation, anemia, synovitis, gout, ankylosing spondylitis,restenosis, periodontal disease, epidermolysis bullosa, osteoporosis,loosening of artificial joint implants, atherosclerosis (includingatherosclerotic plaque rupture), aortic aneurysm (including abdominalaortic aneurysm and brain aortic aneurysm), periarteritis nodosa,congestive heart failure, myocardial infarction, stroke, cerebralischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerativedisorders (acute and chronic), autoimmune disorders, Huntington'sdisease, Parkinson's disease, migraine, depression, peripheralneuropathy, pain (including low back and neck pain, headache andtoothache), gingivitis, cerebral amyloid angiopathy, nootropic orcognition enhancement, amyotrophic lateral sclerosis, multiplesclerosis, ocular angiogenesis, corneal injury, macular degeneration,conjunctivitis, abnormal wound healing, muscle or joint sprains orstrains, tendonitis, skin disorders (such as psoriasis, eczema,scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis,bursitis, burns, diabetes (including types I and II diabetes, diabeticretinopathy, neuropathy and nephropathy), tumor invasion, tumor growth,tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases(such as AIDS in humans and FLV, FIV in cats), sepsis, premature labor,hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet'ssyndrome, hypersensitivity, kidney disease, Rickettsial infections (suchas Lyme disease, Erlichiosis), Protozoan diseases (such as malaria,giardia, coccidia), reproductive disorders (preferably in livestock) andseptic shock (preferably arthritis, fever, common cold, pain and cancer)in a mammal, preferably a human, cat, livestock or a dog, comprising anamount of a compound of formula I or a pharmaceutically acceptable saltthereof effective in such treatment and a pharmaceutically acceptablecarrier.

[0121] The present invention also relates to a pharmaceuticalcomposition for the treatment of a condition that can be treated byselectively inhibiting COX-2 in a mammal, preferably a human, cat,livestock or dog, comprising a COX-2 selective inhibiting effectiveamount of a compound of formula I or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.

[0122] The present invention also relates to a pharmaceuticalcomposition for the treatment of a condition selected from the groupconsisting of inflammatory diseases such as arthritis (includingosteoarthritis, degenerative joint disease, spondyloarthropathies, goutyarthritis, systemic lupus erythematosus, juvenile arthritis andrheumatoid arthritis), or fever (including rheumatic fever and feverassociated with influenza).

[0123] The present invention also relates to a method for treating acondition selected from the group consisting of arthritis (includingosteoarthritis, degenerative joint disease, spondyloarthropathies, goutyarthritis, systemic lupus erythematosus, juvenile arthritis andrheumatoid arthritis), fever (including rheumatic fever and feverassociated with influenza and other viral infections), common cold,dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn'sdisease, emphysema, acute respiratory distress syndrome, asthma,bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease,organ transplant toxicity, cachexia, allergic reactions, allergiccontact hypersensitivity, cancer (such as solid tumor cancer includingcolon cancer, breast cancer, lung cancer and prostrate cancer;hematopoietic malignancies including leukemias and lymphomas; Hodgkin'sdisease; aplastic anemia, skin cancer and familiar adenomatouspolyposis), tissue ulceration, peptic ulcers, gastritis, regionalenteritis, ulcerative colitis, diverticulitis, recurrentgastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia,synovitis, gout, ankylosing spondylitis, restenosis, periodontaldisease, epidermolysis bullosa, osteoporosis, loosening of artificialjoint implants, atherosclerosis (including atherosclerotic plaquerupture), aortic aneurysm (including abdominal aortic aneurysm and brainaortic aneurysm), periarteritis nodosa, congestive heart failure,myocardial infarction, stroke, cerebral ischemia, head trauma, spinalcord injury, neuralgia, neuro-degenerative disorders (acute andchronic), autoimmune disorders, Huntington's disease, Parkinson'sdisease, migraine, depression, peripheral neuropathy, pain (includinglow back and neck pain, headache and toothache), gingivitis, cerebralamyloid angiopathy, nootropic or cognition enhancement, amyotrophiclateral sclerosis, multiple sclerosis, ocular angiogenesis, cornealinjury, macular degeneration, conjunctivitis, abnormal wound healing,muscle or joint sprains or strains, tendonitis, skin disorders (such aspsoriasis, eczema, scleroderma and dermatitis), myasthenia gravis,polymyositis, myositis, bursitis, burns, diabetes (including types I andII diabetes, diabetic retinopathy, neuropathy and nephropathy), tumorinvasion, tumor growth, tumor metastasis, corneal scarring, scleritis,immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats),sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis,sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease,Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoandiseases (such as malaria, giardia, coccidia), reproductive disorders(preferably in livestock) and septic shock (preferably arthritis, fever,common cold, pain and cancer) in a mammal, preferably a human, cat,livestock or a dog, comprising administering to said mammal an amount ofa compound of formula I or a pharmaceutically acceptable salt thereofeffective in treating such a condition.

[0124] The present invention also relates to a method for treating adisorder or condition that can be treated by selectively inhibitingCOX-2 in a mammal, preferably a human, cat, livestock or a dog,comprising administering to a mammal requiring such treatment a COX-2selective inhibiting effective amount of a compound of formula I or apharmaceutically acceptable salt thereof.

[0125] The present invention also relates to a method for treating acondition selected from the group consisting of inflammatory diseasessuch as arthritis (including osteoarthritis, degenerative joint disease,spondyloarthropathies, gouty arthritis, systemic lupus erythematosus,juvenile arthritis and rheumatoid arthritis), or fever (includingrheumatic fever and fever associated with influenza).

[0126] The term “treating”, as used herein, refers to reversing,alleviating, inhibiting the progress of, or preventing the disorder orcondition to which such term applies, or one or more symptoms of suchdisorder or condition. The term “treatment”, as used herein, refers tothe act of treating, as “treating” is defined immediately above.

[0127] The term “livestock animals” as used herein refers todomesticated quadrupeds, which includes those being raised for meat andvarious byproducts, e.g., a bovine animal including cattle and othermembers of the genus Bos, a porcine animal including domestic swine andother members of the genus Sus, an ovine animal including sheep andother members of the genus Ovis, domestic goats and other members of thegenus Capra; domesticated quadrupeds being raised for specialized taskssuch as use as a beast of burden, e.g., an equine animal includingdomestic horses and other members of the family Equidae, genus Equus, orfor searching and sentinel duty, e.g., a canine animal includingdomestic dogs and other members of the genus Canis; and domesticatedquadrupeds being raised primarily for recreational purposes, e.g.,members of Equus and Canis, as well as a feline animal includingdomestic cats and other members of the family Felidae, genus Felis.

[0128] The term “selective” as used herein, refers to COX-1/COX-2 IC₅₀inhibition ratio of 5 or greater as determined for one of the in vitro,in vivo, or ex vivo assays described on pages 36-41.

[0129] The term “Companion animals” as used herein refers to cats, dogsand horses. As used herein, the term “dog(s)” denotes any member of thespecies Canis familiaris, of which there are a large number of differentbreeds. While laboratory determinations of biological activity may havebeen carried out using a particular breed, it is contemplated that theinhibitory compounds of the present invention will be found to be usefulfor treating pain and inflammation in any of these numerous breeds. Dogsrepresent a particularly preferred class of patients in that they arewell known as being very susceptible to chronic inflammatory processessuch as osteoarthritis and degenerative joint disease, which in dogsoften results from a variety of developmental diseases, e.g., hipdysplasia and osteochondrosis, as well as from traumatic injuries tojoints. Conventional NSAIDs, if used in canine therapy, have thepotential for serious adverse gastrointestinal reactions and otheradverse reactions including kidney and liver toxicity. Gastrointestinaleffects such as single or multiple ulcerations, including perforationand hemorrhage of the esophagus, stomach, duodenum or small and largeintestine, are usually debilitating, but can often be severe or evenfatal.

[0130] The term “treating reproductive disorders (preferably inlivestock)” as used herein refers to the use of the COX-2 inhibitors ofthe invention in mammals, preferably livestock animals (cattle, pigs,sheep, goats or horses), during the estrus cycle to control the time ofonset of estrus by blocking the uterine signal for lysis of the corpusluteum, i.e. F-series prostaglandins, then removing the inhibition whenthe onset of estrus is desired. There are settings where it is useful tocontrol or synchronize the time of estrus, especially when artificialinsemination or embryo transfer are to be performed. Such use alsoincludes enhancing the rate of embryo survival in pregnant livestockanimals. Blocking F-series prostaglandin release can have severalbeneficial actions including reducing uterine contractions, enhancinguteroplacental bloodflow, supporting recognition of pregnancy andpostponing lysis of the corpus luteum at the time when estrus would haveoccurred had the animal not become pregnant (around Day 21 ofpregnancy). Such treatment also abrogates the effects of stress onreproduction. For example reductions in fertility caused by excessiveheat, negative energy balance and other stresses which have a COX-2mediated component, as does abortion induced by stress such as heat,transportation, co-mingling, palpation, infection, etc. Such treatmentis also useful to control the time of parturition, which is accompaniedby release of F-series prostaglandins that lead to lysis of the corpusluteum. Inhibition of COX-2 would block the onset of premature labor inlivestock animals, allowing the offspring time to mature before birth.Also there are settings where controlling the time of parturition is auseful tool for management of pregnant animals.

[0131] The subject invention also includes isotopically-labelledcompounds, which are identical to those recited in Formula I, but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively.Compounds of the present invention, prodrugs thereof andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of Formula I of this invention andprodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

[0132] This invention also encompasses pharmaceutical compositionscontaining prodrugs of compounds of the formula I. This invention alsoencompasses methods of treating disorders that can be treated by theselective inhibition of COX-2 comprising administering prodrugs ofcompounds of the formula I. Compounds of formula I having free amino,amido, hydroxy, carboxylic acid ester, sulfonamide or carboxylic groups(especially alkyl-S— and alkyl-(S═O)—) can be converted into prodrugs.Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues which are covalently joined through peptide bonds to freeamino, hydroxy or carboxylic acid groups of compounds of formula I. Theamino acid residues include the 20 naturally occurring amino acidscommonly designated by three letter symbols and also include,4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters are covalently bonded to the above substituents offormula I through the carbonyl carbon prodrug sidechain. Prodrugs alsoinclude metabolically labile groups such as ethers, acetates, mercaptansand sulfoxides.

[0133] One of ordinary skill in the art will appreciate that thecompounds of the invention are useful in treating a diverse array ofdiseases. One of ordinary skill in the art will also appreciate thatwhen using the compounds of the invention in the treatment of a specificdisease that the compounds of the invention may be combined with variousexisting therapeutic agents used for that disease.

[0134] For the treatment of rheumatoid arthritis, the compounds of theinvention may be combined with agents such as TNF-α inhibitors such asanti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules(such as Enbrel®), low dose methotrexate, lefunimide,hydroxychloroquine, d-penicilamine, auranofin or parenteral or oralgold.

[0135] The compounds of the invention can also be used in combinationwith existing therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAID's) such as piroxicam,diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, COX-2 inhibitors such as celecoxib androfecoxib, analgesics and intraarticular therapies such ascorticosteroids and hyaluronic acids such as hyalgan and synvisc.

[0136] This invention also relates to a method of or a pharmaceuticalcomposition for treating inflammatory processes and diseases comprisingadministering a compound of formula I of this invention or its salt to amammal including a human, cat, livestock or dog, wherein saidinflammatory processes and diseases are defined as above and saidinhibitory compound is used in combination with one or more othertherapeutically active agents under the following conditions:

[0137] A.) where a joint has become seriously inflammed as well asinfected at the same time by bacteria, fungi, protozoa and/or virus,said inhibitory compound is administered in combination with one or moreantibiotic, antifungal, antiprotozoal and/or antiviral therapeuticagents;

[0138] B.) where a multi-fold treatment of pain and inflammation isdesired, said inhibitory compound is administered in combination withinhibitors of other mediators of inflammation, comprising one or moremembers independently selected from the group consisting essentially of:

[0139] (1) NSAIDs;

[0140] (2) H₁-receptor antagonists;

[0141] (3) kinin-B₁- and B₂-receptor antagonists;

[0142] (4) prostaglandin inhibitors selected from the group consistingof PGD-, PGF-PGI₂- and PGE-receptor antagonists;

[0143] (5) thromboxane A₂ (TXA₂—) inhibitors;

[0144] (6) 5-, 12- and 15-lipoxygenase inhibitors;

[0145] (7) leukotriene LTC₄—, LTD₄/LTE₄- and LTB₄-inhibitors;

[0146] (8) PAF-receptor antagonists;

[0147] (9) gold in the form of an aurothio group together with one ormore hydrophilic groups;

[0148] (10) immunosuppressive agents selected from the group consistingof cyclosporine, azathioprine and methotrexate;

[0149] (11) anti-inflammatory glucocorticoids;

[0150] (12) penicillamine;

[0151] (13) hydroxychloroquine;

[0152] (14) anti-gout agents including colchicine; xanthine oxidaseinhibitors including allopurinol; and uricosuric agents selected fromprobenecid, sulfinpyrazone and benzbromarone;

[0153] C. where older mammals are being treated for disease conditions,syndromes and symptoms found in geriatric mammals, said inhibitorycompound is administered in combination with one or more membersindependently selected from the group consisting essentially of:

[0154] (1) cognitive therapeutics to counteract memory loss andimpairment;

[0155] (2) anti-hypertensives and other cardiovascular drugs intended tooffset the consequences of atherosclerosis, hypertension, myocardialischemia, angina, congestive heart failure and myocardial infarction,selected from the group consisting of:

[0156] a. diuretics;

[0157] b. vasodilators;

[0158] c. β-adrenergic receptor antagonists;

[0159] d. angiotensin-II converting enzyme inhibitors (ACE-inhibitors),alone or optionally together with neutral endopeptidase inhibitors;

[0160] e. angiotensin II receptor antagonists;

[0161] f. renin inhibitors;

[0162] g. calcium channel blockers;

[0163] h. sympatholytic agents;

[0164] i. α₂-adrenergic agonists;

[0165] j. α-adrenergic receptor antagonists; and

[0166] k. HMG-CoA-reductase inhibitors (anti-hypercholesterolemics);

[0167] (3) antineoplastic agents selected from:

[0168] a. antimitotic drugs selected from:

[0169] i. vinca alkaloids selected from:

[0170] [1] vinblastine and

[0171] [2] vincristine;

[0172] (4) growth hormone secretagogues;

[0173] (5) strong analgesics;

[0174] (6) local and systemic anesthetics; and

[0175] (7) H₂-receptor antagonists, proton pump inhibitors and othergastroprotective agents.

[0176] The active ingredient of the present invention may beadministered in combination with inhibitors of other mediators ofinflammation, comprising one or more members selected from the groupconsisting essentially of the classes of such inhibitors and examplesthereof which include, matrix metalloproteinase inhibitors, aggrecanaseinhibitors, TACE inhibitors, leucotriene receptor antagonists, IL-1processing and release inhibitors, ILra, H₁-receptor antagonists;kinin-B₁- and B₂-receptor antagonists; prostaglandin inhibitors such asPGD-, PGF-PGI₂- and PGE-receptor antagonists; thromboxane A₂ (TXA2-)inhibitors; 5- and 12-lipoxygenase inhibitors; leukotriene LTC₄-,LTD₄/LTE₄- and LTB₄-inhibitors; PAF-receptor antagonists; gold in theform of an aurothio group together with various hydrophilic groups;immunosuppressive agents, e.g., cyclosporine, azathioprine andmethotrexate; anti-inflammatory glucocorticoids; penicillamine;hydroxychloroquine; anti-gout agents, e.g., colchicine, xanthine oxidaseinhibitors, e.g., allopurinol and uricosuric agents, e.g., probenecid,sulfinpyrazone and benzbromarone.

[0177] The compounds of the present invention may also be used incombination with anticancer agents such as endostatin and angiostatin orcytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide,taxol, taxotere and alkaloids, such as vincristine and antimetabolitessuch as methotrexate.

[0178] The compounds of the present invention may also be used incombination with anti-hypertensives and other cardiovascular drugsintended to offset the consequences of atherosclerosis, includinghypertension, myocardial ischemia including angina, congestive heartfailure and myocardial infarction, selected from vasodilators such ashydralazine, β-adrenergic receptor antagonists such as propranolol,calcium channel blockers such as nifedipine, α₂-adrenergic agonists suchas clonidine, α-adrenergic receptor antagonists such as prazosin andHMG-CoA-reductase inhibitors (anti-hypercholesterolemics) such aslovastatin or atorvastatin.

[0179] The active ingredient of the present invention may also beadministered in combination with one or more antibiotic, antifungal,antiprotozoal, antiviral or similar therapeutic agents.

[0180] The compounds of the present invention may also be used incombination with CNS agents such as antidepressants (such assertraline), anti-Parkinsonian drugs (such as L-dopa, requip, mirapex,MAOB inhibitors such as selegine and rasagiline, comP inhibitors such asTasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists,nicotine agonists, dopamine agonists and inhibitors of neuronal nitricoxide synthase) and anti-Alzheimer's drugs such as donepezil, tacrine,COX-2 inhibitors, propentofylline or metryfonate.

[0181] The compounds of the present invention may also be used incombination with osteoporosis agents such as roloxifene, lasofoxifene,droloxifene or fosomax and immunosuppressant agents such as FK-506 andrapamycin.

[0182] The present invention also relates to the formulation of theactive agents of the present invention alone or with one or more othertherapeutic agents which are to form the intended combination, includingwherein said different drugs have varying half-lives, by creatingcontrolled-release forms of said drugs with different release timeswhich achieves relatively uniform dosing; or, in the case of non-humanpatients, a medicated feed dosage form in which said drugs used in thecombination are present together in admixture in said feed composition.There is further provided in accordance with the present inventionco-administration in which the combination of drugs is achieved by thesimultaneous administration of said drugs to be given in combination;including co-administration by means of different dosage forms androutes of administration; the use of combinations in accordance withdifferent but regular and continuous dosing schedules whereby desiredplasma levels of said drugs involved are maintained in the patient beingtreated, even though the individual drugs making up said combination arenot being administered to said patient simultaneously.

DETAILED DESCRIPTION OF THE INVENTION

[0183] The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated, the ringof the formula (R⁵)-A-(SO_(m)R⁴), m, X, and R¹ through R⁶ in thereaction schemes and discussion that follow are as defined above.

[0184] Scheme 1 refers to the preparation of a compound of formula I.

[0185] Referring to Scheme 1, a compound of formula I (Le., a compoundof the formulae IA1-IA7, respectively):

[0186] can be prepared by reacting a compound of formula II, i.e., acompound of formulae IIA1-IIA7, respectively:

[0187] wherein R⁷ is a leaving group, with a compound of the formulaR³—B—H in the presence of a fluoride containing salt and in the presenceof a solvent.

[0188] The above compounds of the formula R³—B—H are commerciallyavailable or can be prepared by the methods described in Jerry March,“Advanced Organic Chemistry”, 4th edition, 1992, and references citedtherein.

[0189] Suitable leaving groups R⁷ of the compound of formula II includehalo, such as fluoro, chloro, iodo, or bromo. Other suitable leavinggroups include (C₁-C₆)alkyl-SO₃—, such as CH₃—SO₃—, CF₃—SO₃—, orCF₃CF₂—SO₃—. Other suitable leaving groups include (C₆-C₁₀)aryl-SO₃—,such as tosyl-SO₃— or phenyl-SO₃—. Other suitable leaving groups include(C₁-C₆)alkyl-SO₂—, such as CH₃—SO₂—; or (C₆-C₁₀)aryl-SO₂—, such asphenyl-SO₂—. Preferably, the leaving group R⁷ is halo, such as chloro;or (C₁-C₆)alkyl-SO₃—, such as CF₃—SO₃—, or CF₃CF₂—SO₃—.

[0190] Suitable fluoride containing salts include a metal salt, such aslithium, sodium, potassium, cesium, magnesium, calcium, strontium andbarium. Other suitable fluoride salts include tetra(C₁-C₈)alkylammoniumfluoride, such as tetrabutylammonium fluoride; or(C₁-C₁₆)alkyltri(C₁-C₂)alkylammonium fluoride, such ascetyltrimethylammonium fluoride.

[0191] The aforesaid reaction can be performed in the presence of about0.05 to about 10 equivalents; more preferably about 0.05 to about 5equivalents; most preferably about 0.1 to about 2 equivalents; of thefluoride containing salts relative to the compound of formula I.

[0192] Unless otherwise indicated, the term “equivalents” refers to thenumber of moles of the fluoride containing salt relative to the numberof moles of the compound of the formula I.

[0193] Suitable solvents used in the aforesaid reaction includeacetonitrile, dichloromethane, chloroform, tetrahydrofuran,dichloroethane, dimethylsulfoxide, dimethylformamide, dimethylacetamide,or acetone.

[0194] The aforesaid reaction can be performed at a temperature of about10° C. to about 100° C., preferably about 20° C. to about 80° C. Theaforesaid reaction can be performed for a period from about 2 hours toabout 96 hours, preferably from about 12 hours to about 48 hours.

[0195] In the aforesaid reaction, when the fluoride containing salt is ametal salt such as potassium fluoride or cesium fluoride; preferredsolvents include dimethylsulfoxide, dimethylformamide,dimethylacetamide, acetone, or acetonitrile. Preferably, the aforesaidreaction is performed at a temperature of about 10° C. to about 30° C.Preferably, the aforesaid reaction is performed in the presence of about0.05 to about 5 equivalents of the fluoride containing salts relative tothe compound of formula I.

[0196] In the aforesaid reaction, when the fluoride containing salt istetra(C₁-C₈)alkylammonium fluoride or(C₁-C₁₆)alkyltri(C₁-C₂)alkylammonium fluoride; preferred solventsinclude acetonitrile, dichloromethane, chloroform, tetrahydrofuran, ordichloroethane. Preferably, the aforesaid reaction is performed at atemperature of about 20° C. to about 80° C. Preferably, the aforesaidreaction is performed in the presence of about 0.1 to about 2equivalents of the fluoride containing salts relative to the compound offormula I.

[0197] Scheme 2 illustrates methods of preparing compounds of theformula II, which are intermediates useful in preparing compounds of theformula I in Scheme 1.

[0198] Referring to Scheme 2, a compound of the formula II wherein R⁷ ishalo can be prepared by reacting a compound of the formula III with ahalogenating agent in a polar solvent. Suitable halogenating agentsinclude oxalyl chloride, POCl₃, POBr₃, SOCl₂ or PCl₅, preferably POCl₃.Suitable solvents include methylene chloride, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP),preferably methylene chloride. The aforesaid reaction is generallycarried out at a temperature from about 20° C. to about 140° C.,preferably at about the reflux temperature of the polar solvent,preferably when the solvent is methylene chloride, the temperature is55° C. The aforesaid reaction is generally carried out for a period fromabout 1 hour to about 48 hours, preferably about 2 hours to about 24hours.

[0199] A compound of the formula II wherein R⁷ contains a —SO₃—, such as(C₁-C₆)alkyl-SO₃— or (C₆-C₁₀)aryl-SO₃—, can be prepared by reacting acompound of the formula III with a sulfonylating agent in a polarsolvent. Suitable sulfonylating agents include trifluoromethanesulfonicanhydride, methanesulfonyl chloride, or methanesulfonyl anhydride,preferably methanesulfonyl chloride. Suitable solvents for the aforesaidreaction include methylene chloride, N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP),preferably methylene chloride. The aforesaid reaction is generallycarried out at a temperature from about −10° C. to about 25° C.,preferably at about 0° C. The aforesaid reaction is generally carriedout for a period from about 1 hour to about 48 hours.

[0200] A compound of the formula II wherein said R⁷ contains a —SO₂—,such as (C₁-C₆)alkyl-SO₂— or (C₆-C₁₀)aryl-SO₂—, can be prepared byreacting a compound of the formula II wherein R⁷ is halo or contains a—SO₃—, as defined above, with a sulfonating agent in a polar solvent.Suitable sulfonating agents include NaSO₃CH₃ or NaSO₃(C₆-C₁₀)aryl. Othersuitable sulfonating agents include NaS(C₁-C₆)alkyl, such as NaSCH₃, orNaS(C₆-C₁₀)aryl, such as NaS(C₆H₅), followed by an oxidizing agent, suchas OXONE®, metachloroperbenzoic acid, or hydrogen peroxide. Suitablesolvents for the aforesaid reaction include DMF, DMA, or DMSO,preferably DMSO. The aforesaid reaction is generally carried out at atemperature from about minus 10° C. to about 120° C., preferably atabout 100° C. The aforesaid reaction is generally carried out for aperiod from about 1 hour to about 48 hours, preferably about 4 hours toabout 24 hours.

[0201] Compounds of the formula III can be prepared by reacting acompound of formula IV, wherein the ring of the formula(R⁵)-A-(SO_(m)R⁴) is as defined above, with a reagent of the formula

[0202] wherein R is (C₁-C₆)alkyl, such as methyl; in a suitable solventunder acidic, neutral or basic conditions. Preferably, the reagent is4,4,4-trifluoro-3-oxo-butyric acid methyl ester. Suitable solventsinclude methanol, ethanol, DMF, DMSO, water or a mixture thereof.Suitable acids include hydrochloric acid or trifluoroacetic acid.Suitable bases include sodium hydroxide, potassium hydroxide andpotassium carbonate. The aforesaid reaction is generally carried out ata temperature from about 0° C. to about 140° C., preferably at about 20°C. to about 100° C., most preferably at about 20° C. to about 100° C.The aforesaid reaction is generally carried out for a period from about1 hour to about 24 hours, preferably from about 6 hours to about 16hours.

[0203] The above reagents of formula R²—(C═O)—CH(R¹)—(C═O)—OR arecommercially available or can be prepared according to the methodsdescribed in Jerry March, “Advanced Organic Chemistry”, 4th edition,1992, and references cited therein.

[0204] Compounds of formula IV are commercially available or can be madeby methods well known to those of ordinary skill in the art or accordingto Scheme 3. For example, compounds of formula IV can be prepared by themethod described in Vavrina, et al,. Collection Czechoslov. Chem.Commun., Vol. 37, 1721 (1972), which is incorporated herein byreference.

[0205] Scheme 3 refers to a preparation of a compound of the formula IV,which are intermediates useful in preparing compounds of the formula IIin Scheme 2.

[0206] Referring to Scheme 3, a compound of the formula IV (i.e., acompound of the formulae IVA1-IVA7, respectively):

[0207] wherein m is 1, or 2, can be prepared by reacting a compound ofthe formula V (i.e., a compound of the formulae VA1-VA7, respectively):

[0208] wherein L² is a leaving group and m is 1 or 2, with hydrazine(preferably anhydrous hydrazine) in the presence of a polar solvent.Suitable leaving groups L include halo, triflate, or methylsulfonyl,preferably halo, such as chloro and bromo. Suitable solvents includealcohol (such as ethanol, methanol, propanol or butanol), DMSO, DMF,DMA, or NMP, preferably alcohol, most preferably ethanol. This reactioncan be carried out at a temperature from about 0° C. to about 140° C.,preferably at about the reflux temperature of the solvent. This reactioncan be carried out for a period of from about 1 hour to about 36 hours,preferably from about 2 hours to about 24 hours. Preferably the productis isolated as a salt, such as a hydrobromide or hydrochloride salt. Thehydrochloride salt is preferred.

[0209] The compound of the formula IV wherein m is 0 can be prepared byreacting a compound of the formula VI (i.e., a compound of the formulaeVIA1-VIA7, respectively):

[0210] wherein L² is a leaving group, with hydrazine (preferablyanhydrous hydrazine) in the presence of a polar solvent, under thecondition described in the aforesaid paragraph.

[0211] The compound of the formula V (i.e., a compound of the formulaeVA1-VA7, respectively, as defined above) can be prepared by reacting acompound of the formula VI (i.e., a compound of the formulae VIA1-VIA7,respectively, as defined above), wherein L is a leaving group, with anoxidizing reagent in the presence of a solvent. Suitable oxidizingagents include meta-chloroperbenzoic acid, hydrogen peroxide, sodiumperborate, or OXONE®, preferably OXONE®. Suitable solvents or solventmixtures include methanol-water, dioxane-water, tetrahydrofuran-water,methylene chloride, or chloroform, preferably methanol-water ormethylene chloride. The aforesaid reaction can be carried out at atemperature from about 0° C. to about 60° C., preferably the temperaturemay range from about 20° C. to about 25° C. (i.e. room temperature). Theaforesaid reaction can be carried out for a period of from about 0.5hours to about 24 hours, preferably about 16 hours.

[0212] The compounds of the formula VI (i.e., a compound of the formulaeVIA1-VIA7, respectively, as defined above) can be prepared from acompound of formula VII (i.e., a compound of the formulae VIIA1-VIIA7,respectively):

[0213] wherein each of L¹ and L² independently is a leaving group, byreacting said compound of the formula VII with a sulfur reagent in thepresence or absence of a base in a polar solvent. Suitable leavinggroups L¹ include halo or methyl-SO₂—, preferably halo, such as bromo oriodo. Suitable leaving groups L² halo or methyl-SO₂—, preferably halo,such as bromo or iodo. Suitable sulfur reagents include (C₁-C₆)alkyl-SH,(C₁-C₆)alkyl-S—S—(C₁-C₆)alkyl, (C₁-C₆)alkyl-SO₃—, NaS-(C₁-C₆)alkyl orKS-(C₁-C₆)alkyl. Suitable bases include sodium hydroxide, triethylamine,alkyllithiums (such as n-butyllithium, sec-butyllithium andtert-butyllithium) and lithium diisopropylamide. Suitable solventsinclude dialkylethers (such as dimethylether), alcohol (such asmethanol, ethanol and tert-butanol), THF, benzene, toluene, xylene, DMF,DMSO, dioxane, 1,2-dimethoxyethane and a mixture of an alcohol andwater. The aforesaid reaction can be carried out at a temperature fromabout −78° C. to 200° C., preferably the temperature may range fromabout −78° C. to about 120° C. The aforesaid reaction can be carried outfor a period of from about 1 minute to about 24 hours.

[0214] Compounds of the formula VII (i.e., a compound of the formulaeVIIA1-VIIA7, respectively, as defined above) may be prepared by methodswell known to those of ordinary skill in the art (see for example, EP1104760).

[0215] Unless indicated otherwise, the pressure of each of the abovereactions is not critical. Generally, the reactions will be conducted ata pressure of about one to about three atmospheres, preferably atambient pressure (about one atmosphere).

[0216] Those skilled in the art will appreciate that the above schemesdescribe general methods for preparing the compounds of the invention.Specific compounds of formula I may possess sensitive functional groupsthat require protecting groups when prepared with the intermediatesdescribed. Examples of suitable protecting groups may be found in T. W.Greene and P. Wuts, Protecting Groups in Organic Synthesis, John Wiley &Sons, 2nd Edition, New York, 1991.

[0217] The compounds of the formula I which are basic in nature arecapable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate a compound of the formula Ifrom the reaction mixture as a pharmaceutically unacceptable salt andthen simply convert the latter back to the free base compound bytreatment with an alkaline reagent, and subsequently convert the freebase to a pharmaceutically acceptable acid addition salt. The acidaddition salts of the base compounds of this invention are readilyprepared by treating the base compound with a substantially equivalentamount of the chosen mineral or organic acid in an aqueous solventmedium or in a suitable organic solvent such as methanol or ethanol.Upon careful evaporation of the solvent, the desired solid salt isobtained.

[0218] The acids which are used to prepare the pharmaceuticallyacceptable acid addition salts of the base compounds of this inventionare those which form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

[0219] Those compounds of the formula I which are also acidic in natureare capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the herein described acidic compounds offormula I. These non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium, calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum product yields.

[0220] Method for Assessing Biological Activities:

[0221] The activity of the compounds of the formula I of the presentinvention may be demonstrated by the following assays.

[0222] Human in vitro Assays

[0223] Human Cell-Based COX-1 Assay

[0224] Human peripheral blood obtained from healthy volunteers can bediluted to {fraction (1/10)} volume with 3.8% sodium citrate solution.The platelet-rich plasma immediately obtained can be washed with 0.14 Msodium chloride containing 12 mM Tris-HCl (pH 7.4) and 1.2 mM EDTA.Platelets can then be washed with platelet buffer (Hanks buffer (Cafree) containing 0.2% BSA and 20 mM Hepes). Finally, the human washedplatelets (HWP) can be suspended in platelet buffer at the concentrationof 2.85×10⁸ cells/ml and stored at room temperature until use. The HWPsuspension (70 μl aliquots, final 2.0×10⁷ cells/ml) can be placed in a96-well U bottom plate and 10 μl aliquots of 12.6 mM calcium chlorideadded. Platelets can be incubated with A23187 (final 10 μM, Sigma) withtest compound (0.1-100 μM) dissolved in DMSO (final concentration; lessthan 0.01%) at 37° C. for 15 minutes. The reaction can be stopped byaddition of EDTA (final 7.7 mM) and TxB2 in the supernatant quantitatedby using a radioimmunoassay kit (Amersham) according to themanufacturer's procedure.

[0225] Human Cell-Based COX-2 Assay

[0226] The human cell based COX-2 assay can be carried out as previouslydescribed (Moore et al., Inflam. Res., 45, 54, 1996). Confluent humanumbilical vein endothelial cells (HUVECs, Morinaga) in a 96-well flatbottom plate can be washed with 80 ml of RPMI1640 containing 2% FBS andincubated with hIL-1β (final concentration 300 U/ml, R & D Systems) at37° C. for 24 hours. After washing, the activated HUVECs can beincubateed with test compound (final concentration; 0.1 nM-1 LM)dissolved in DMSO (final concentration; less than 0.01%) at 37° C. for20 minutes and stimulated with A23187 (final concentration 30 mM) inHanks buffer containing 0.2% BSA, 20 mM Hepes at 37° C. for 15 minutes.6-Keto-PGF_(1α), stable metabolite of PGI2, in the supernatant can bequantitated by using a radioimmunoassay method (antibody; PreseptiveDiagnostics, SPA; Amersham).

[0227] Canine in vitro Assays

[0228] The following canine cell based COX 1 and COX-2 assays have beenreported in Ricketts et al., Evaluation of Selective Inhibition ofCanine Cyclooxygenase 1 and 2 by Carprofen and Other NonsteroidalAnti-inflammatory Drugs, American Journal of Veterinary Research, 59(11), 1441-1446.

[0229] Protocol for Evaluation of Canine COX-1 Activity

[0230] Test drug compounds can be solubilized and diluted the day beforethe assay can be to be conducted with 0.1 mL of DMSO/9.9 mL of Hank'sbalanced salts solution (HBSS) and stored overnight at 4° C. On the daythat the assay can be carried out, citrated blood can be drawn from adonor dog, centrifuged at 190×g for 25 minutes at room temperature andthe resulting platelet-rich plasma can then be transferred to a new tubefor further procedures. The platelets can be washed by centrifuging at1500×g for 10 minutes at room temperature. The platelets can be washedwith platelet buffer comprising Hank's buffer (Ca free) with 0.2% bovineserum albumin (BSA) and 20 mM HEPES. The platelet samples can then beadjusted to 1.5×10⁷/mL, after which 50 μl of calcium ionophore (A23187)together with a calcium chloride solution can be added to 50 μl of testdrug compound dilution in plates to produce final concentrations of 1.7μM A23187 and 1.26 mM Ca. Then, 100 μl of canine washed platelets can beadded and the samples can be incubated at 37° C. for 15 minutes, afterwhich the reaction can be stopped by adding 20 μl of 77 mM EDTA. Theplates can then be centrifuged at 2000×g for 10 minutes at 4° C., afterwhich 50 μl of supernatant can be assayed for thromboxane B₂ (TXB₂) byenzyme-immunoassay (EIA). The pg/mL of TXB₂ can be calculated from thestandard line included on each plate, from which it can be possible tocalculate the percent inhibition of COX-1 and the IC₅₀ values for thetest drug compounds.

[0231] Protocol for Evaluation of Canine COX-2 Activity

[0232] A canine histocytoma (macrophage-like) cell line from theAmerican Type Culture Collection designated as DH82, can be used insetting up the protocol for evaluating the COX-2 inhibition activity ofvarious test drug compounds. There can be added to flasks of these cells10 μg/mL of LPS, after which the flask cultures can be incubatedovernight. The same test drug compound dilutions as described above forthe COX-1 protocol can be used for the COX-2 assay and can be preparedthe day before the assay can be carried out. The cells can be harvestedfrom the culture flasks by scraping and can then be washed with minimalEagle's media (MEM) combined with 1% fetal bovine serum, centrifuged at1500 rpm for 2 minutes and adjusted to a concentration of 3.2×10⁵cells/mL. To 50 μl of test drug dilution there can be added 50 μl ofarachidonic acid in MEM to give a 10 μM final concentration and therecan be added as well 100 μl of cell suspension to give a finalconcentration of 1.6×10⁵ cells/mL. The test sample suspensions can beincubated for 1 hour and then centrifuged at 1000 rpm for 10 minutes at4° C., after which 50 PI aliquots of each test drug sample can bedelivered to EIA plates. The EIA can be performed for prostaglandin E₂(PGE₂) and the pg/mL concentration of PGE₂ can be calculated from thestandard line included on each plate. From this data it can be possibleto calculate the percent inhibition of COX-2 and the IC₅₀ values for thetest drug compounds. Repeated investigations of COX-1 and COX-2inhibition can be conducted over the course of several months. Theresults are averaged and a single COX-1: COX-2 ratio is calculated.

[0233] Whole blood assays for COX-1 and COX-2 are known in the art suchas the methods described in C. Brideau, et al., A Human Whole BloodAssay for Clinical Evaluation of Biochemical Efficacy of CyclooxygenaseInhibitors, Inflammation Research, Vol. 45, pp. 68-74 (1996). Thesemethods may be applied with feline, canine or human blood as needed.

[0234] In vivo Assays

[0235] Carrageenan Induced Foot Edema in Rats

[0236] Male Sprague-Dawley rats (5 weeks old, Charles River Japan) canbe fasted overnight. A line can be drawn using a marker above the ankleon the right hind paw and the paw volume (V0) can be measured by waterdisplacement using a plethysmometer (Muromachi). Animals can be givenorally either vehicle (0.1% methyl cellulose or 5% Tween 80) or a testcompound (2.5 ml per 100 g body weight). One hour later, the animals canthen be injected intradermally with λ-carrageenan (0.1 ml of 1% w/vsuspension in saline, Zushikagaku) into right hind paw (Winter et al.,Proc. Soc. Exp. Biol. Med., 111, 544, 1962; Lombardino et al., Arzneim.Forsch., 25, 1629, 1975) and three hours later, the paw volume (V3) canbe measured and the increase in volume (V3-V0) calculated. Since maximuminhibition attainable with classical NSAIDs is 60-70%, ED₃₀ values canbe calculated.

[0237] Gastric Ulceration in Rats

[0238] The gastric ulcerogenicity of test compound can be assessed by amodification of the conventional method (Ezer et al., J. Pharm.Pharmacol., 28, 655, 1976; Cashin et al., J. Pharm. Pharmacol., 29,330-336, 1977). Male Sprague-Dawley rats (5 weeks old, Charles RiverJapan), fasted overnight, can be given orally either vehicle (0.1%methyl cellulose or 5% Tween 80) or a test compound (1 ml per 10 g bodyweight). Six hours after, the animals can be sacrificed by cervicaldislocation. The stomachs can be removed and inflated with 1% formalinsolution (10 ml). Stomachs can be opened by cutting along the greatercurvature. From the number of rats that showed at least one gastriculcer or haemorrhaging erosion (including ecchymosis), the incidence ofulceration can be calculated. Animals did not have access to either foodor water during the experiment.

[0239] Canine Whole Blood ex vivo Determinations of COX-1 and COX-2Activity Inhibition

[0240] The in vivo inhibitory potency of a test compound against COX-1and COX-2 activity may be evaluated using an ex vivo procedure on caninewhole blood. Three dogs can be dosed with 5 mg/kg of the test compoundadministered by oral gavage in 0.5% methylcellulose vehicle and threedogs can be untreated. A zero-hour blood sample can be collected fromall dogs in the study prior to dosing, followed by 2- and 8-hourpost-dose blood sample collections. Test tubes can be preparedcontaining 2 μL of either (A) calcium ionophore A23187 giving a 50 [Mfinal concentration, which stimulates the production of thromboxane B₂(TXB₂) for COX-1 activity determination; or of (B) lipopolysaccharide(LPS) to give a 10 μg/mL final concentration, which stimulates theproduction of prostaglandin E₂ (PGE₂) for COX-2 activity determination.Test tubes with unstimulated vehicle can be used as controls. A 500 μLsample of blood can be added to each of the above-described test tubes,after which they can be incubated at 37° C. for one hour in the case ofthe calcium ionophore-containing test tubes and overnight in the case ofthe LPS-containing test tubes. After incubation, 10 μL of EDTA can beadded to give a final concentration of 0.3%, in order to preventcoagulation of the plasma which sometimes occurs after thawing frozenplasma samples. The incubated samples can be centrifuged at 4° C. andthe resulting plasma sample of ˜200 μL can be collected and stored at−20° C. in polypropylene 96-well plates. In order to determine endpointsfor this study, enzyme immunoassay (EIA) kits available from Cayman canbe used to measure production of TXB₂ and PGE₂, utilizing the principleof competitive binding of tracer to antibody and endpoint determinationby calorimetry. Plasma samples can be diluted to approximate the rangeof standard amounts which would be supplied in a diagnostic or researchtools kit, i.e., {fraction (1/500)} for TXB₂ and {fraction (1/750)} forPGE₂.

[0241] The data set out in Table 1 below show how the percent inhibitionof COX-1 and COX-2 activity is calculated based on their zero hourvalues. The data is expressed as treatment group averages in pg/ml ofTXB₂ and PGE₂ produced per sample. Plasma dilution can be not factoredin said data values.

[0242] The data in Table 1 show that, in this illustration, at the 5mg/kg dose there can be significant COX-2 inhibition at both timepoints.The data in Table 1 also show that at the 5 mg/kg dose there can be nosignificant inhibition of COX-1 activity at the timepoints involved.Accordingly, the data in Table 1 clearly demonstrates that at the 5mg/kg dosage concentration this compound possesses good COX-2selectivity. TABLE 1 COX-1 ACTIVITY INHIBITION—Group Averages TXB₂Pg/mL/Well Percent Inhibition Hour 0-hour 2-hour 8-hour 2-hour 8-hourUntreated 46 45 140 2% 0% 5 mg/kg 41 38 104 7% 0% COX-2 ACTIVITYINHIBITION—Group Averages PGE₂ Pg/mL/Well Percent Inhibition Hour 0-hour2-hour 8-hour 2-hour 8-hour Untreated 420 486 501 0% 0% 5 mg/kg 711 165350 77%  51% 

[0243] COX inhibition is observed when the measured percent inhibitionis greater than that measured for untreated controls. The percentinhibition in the above table is calculated in a straightforward mannerin accordance with the following equation:${\% \quad {{Inhibition}( {2\text{-}{hour}} )}} = \frac{( {{{PGE}_{2}\quad {at}\quad t} = 0} ) - ( {{{PGE}_{2}\quad {at}\quad t} = 2} )}{( {{{PGE}_{2}\quad {at}\quad t} = 0} )}$

[0244] Data Analysis

[0245] Statistical program packages, SYSTAT (SYSTAT, INC.) and StatView(Abacus Cencepts, Inc.) for Macintosh can be used. Differences betweentest compound treated group and control group can be tested for usingANOVA. The IC₅₀ (ED30) values can be calculated from the equation forthe log-linear regression line of concentration (dose) versus percentinhibition.

[0246] Most compounds prepared in the Working Examples as describedhereinafter can be tested by at least one of the methods described aboveand showed IC₅₀ values of 0.001 μM to 3 μM with respect to inhibition ofCOX-2 in either the canine or human assays.

[0247] COX-2 selectivity can be determined by ratio in terms of IC₅₀value of COX-1 inhibition to COX-2 inhibition. In general, it can besaid that a compound showing a COX-1/COX-2 inhibition ratio of more than5 has good COX-2 selectivity.

[0248] The compounds of the formula I of this invention can beadministered via oral, parenteral, anal, buccal or topical routes tomammals (including humans, dogs, cats, horses and livestock).

[0249] In general, these compounds are most desirably administered tohumans in doses ranging from 0.01 mg to 100 mg per kg of body weight perday, although variations will necessarily occur depending upon theweight, sex and condition of the subject being treated, the diseasestate being treated and the particular route of administration chosen.However, a dosage level that is in the range of from 0.1 mg to 10 mg perkg of body weight per day, single or divided dosage is most desirablyemployed in humans for the treatment of abovementioned diseases.

[0250] These compounds are most desirably administered to said non-humanmammals, e.g. dogs, cats, horses or livestock in an amount, expressed asmg per kg of body weight of said member per day, ranging from about 0.01mg/kg to about 20.0 mg/kg/day, preferably from about 0.1 mg/kg to about12.0 mg/kg/day, more preferably from about 0.5 mg/kg to about 10.0mg/kg/day and most preferably from about 0.5 mg/kg to about 8.0mg/kg/day.

[0251] The compounds of the present invention may be administered aloneor in combination with pharmaceutically acceptable carriers or diluentsby either of the above routes previously indicated and suchadministration can be carried out in single or multiple doses. Moreparticularly, the novel therapeutic agents of the invention can beadministered in a wide variety of different dosage forms, i.e., they maybe combined with various pharmaceutically acceptable inert carriers inthe form of tablets, capsules, lozenges, trochees, hard candies,powders, sprays, creams, salves, suppositories, jellies, gels, pastes,lotions, ointments, aqueous suspensions, injectable solutions, elixirs,syrups and the like. Such carriers include solid diluents or fillers,sterile aqueous media and various nontoxic organic solvents, etc.Moreover, oral pharmaceutical compositions can be suitably sweetenedand/or flavored. In general, the therapeutically-effective compounds ofthis invention are present in such dosage forms at concentration levelsranging from 5% to 70% by weight, preferably 10% to 50% by weight.

[0252] For oral administration, tablets containing various excipientssuch as microcrystalline cellulose, sodium citrate, calcium carbonate,dipotassium phosphate and glycine may be employed along with variousdisintegrants such as starch and preferably corn, potato or tapiocastarch, alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatine capsules; preferred materials in this connectionalso include lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyesand, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various combinations thereof.

[0253] A preferred composition for dogs comprises an ingestible liquidperoral dosage form selected from the group consisting of a solution,suspension, emulsion, inverse emulsion, elixir, extract, tincture andconcentrate, optionally to be added to the drinking water of the dogbeing treated. Any of these liquid dosage forms, when formulated inaccordance with methods well known in the art, can either beadministered directly to the dog being treated, or may be added to thedrinking water of the dog being treated. The concentrate liquid form, onthe other hand, is formulated to be added first to a given amount ofwater, from which an aliquot amount may be withdrawn for administrationdirectly to the dog or addition to the drinking water of the dog.

[0254] A preferred composition provides delayed-, sustained- and/orcontrolled-release of said anti-inflammatory selective COX-2 inhibitor.Such preferred compositions include all such dosage forms which produce≧80% inhibition of COX-2 isozyme activity and result in a plasmaconcentration of said inhibitor of at least 3 fold the COX-2 IC₅₀ for atleast 4 hours; preferably for at least 8 hours; more preferably for atleast 12 hours; more preferably still for at least 16 hours; even morepreferably still for at least 20 hours; and most preferably for at least24 hours. Preferably, there is included within the above-describeddosage forms those which produce ≧80% inhibition of COX-2 isozymeactivity and result in a plasma concentration of said inhibitor of atleast 5 fold the COX-2 IC₅₀ for at least 4 hours, preferably for atleast 8 hours, more preferably for at least 12 hours, still morepreferably for at least 20 hours and most preferably for at least 24hours. More preferably, there is included the above-described dosageforms which produce ≧90% inhibition of COX-2 isozyme activity and resultin a plasma concentration of said inhibitor of at least 5 fold the COX-2IC₅₀ for at least 4 hours, preferably for at least 8 hours, morepreferably for at least 12 hours, still more preferably for at least 20hours and most preferably for at least 24 hours.

[0255] For parenteral administration, solutions of a compound of thepresent invention in either sesame or peanut oil or in aqueous propyleneglycol may be employed. The aqueous solutions should be suitablybuffered (preferably pH>8) if necessary and the liquid diluent firstrendered isotonic. These aqueous solutions are suitable for intravenousinjection purposes. The oily solutions are suitable for intra-articular,intramuscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well-known to those skilled in theart. Additionally, it is also possible to administer the compounds ofthe present invention topically when treating inflammatory conditions ofthe skin and this may preferably be done by way of creams, jellies,gels, pastes, ointments and the like, in accordance with standardpharmaceutical practice.

[0256] The compounds of formula I may also be administered in the formof suppositories for rectal or vaginal administration of the activeingredient. These compositions can be prepared by mixing the activeingredient with a suitable non-irritating excipient which is solid atroom temperature (for example, 10° C. to 32° C.) but liquid at therectal temperature and will melt in the rectum or vagina to release theactive ingredient. Such materials are polyethylene glycols, cocoabutter, suppository and wax.

[0257] For buccal administration, the composition may take the form oftablets or lozenges formulated in conventional manner.

[0258] For transdermal administration, transdermal patches prepared inaccordance with well known drug delivery technology may be prepared andapplied to the skin of a mammal, preferably a human or a dog, to betreated, whereafter the active agent by reason of its formulatedsolubility characteristics migrates across the epidermis and into thedermal layers of the skin where it is taken up as part of the generalcirculation, ultimately providing systemic distribution of the activeingredient over a desired, extended period of time. Also included areimplants which are placed beneath the epidermal layer of the skin, i.e.between the epidermis and the dermis of the skin of the patient beingtreated. Such an implant will be formulated in accordance with wellknown principles and materials commonly used in this delivery technologyand may be prepared in such a way as to provide controlled-, sustained-and/or delayed-release of the active ingredient into the systemiccirculation of the patient. Such subepidermal (subcuticular) implantsprovide the same facility of installation and delivery efficiency astransdermal patches, but without the limitation of being subject todegradation, damage or accidental removal as a consequence of beingexposed on the top layer of the patient's skin.

EXAMPLES

[0259] The following examples contain detailed descriptions of themethods of the preparation of compounds of formula I. These detaileddescriptions fall within the scope of the invention and serve toexemplify the above described general synthetic procedures which formpart of the invention. These detailed descriptions are presented forillustrative purposes only and are not intended to restrict the scope ofthe present invention.

[0260] The invention is illustrated in the following non-limitingexamples in which, unless stated otherwise: all operations were carriedout at room or ambient temperature, that is, in the range of 18-25° C.;evaporation of solvent was carried out using a rotary evaporator underreduced pressure with a bath of up to 60° C.; reactions were monitoredby thin layer chromatography (TLC) and analytical column liquidchromatography and reaction times are given for illustration only;melting points (m.p.) given are uncorrected (polymorphism may result indifferent melting points); structure and purity of all isolatedcompounds were assured by at least one of the following techniques: TLC(Merck silica gel 60 F-254 precoated plates), high performance liquidchromatograpy (HPLC), or mass spectrometry. Flash column chromatographywas carried out using Merck silica gel 60 (230-400 mesh ASTM).Preparative HPLC was carried out using Hewlett Packard 1100 LiquidChromatography/Mass Selective Detector (LC/MSD). Separation was done ona Monochrom 5μ CN column PN 0509-250*212 from MetaChem Technologies. Theflow rate was 20 ml/min running a gradient of 0 to 90% of isopropanol inn-hexane. Low-resolution mass spectral data (EI) were obtained on anAutomass 120 (JEOL) mass spectrometer. Liquid Chromatography data wascollected on a Hewlett Packard 1100 Liquid Chromatography/Mass SelectiveDetector (LC/MSD). Analysis was performed on a Luna C-18 column withdimensions of 3.0×150 mm. The flow rate was 0.425 ml/minute running agradient of 50% 0.1% aqueous formic acid and 50% acetonitrile to 100%acetonitrile in 15 minutes. The ionization type for the mass detector ofthe Mass Spectrophotometer was atmospheric pressure electrospray in thepositive ion mode with a fragmentor voltage of 50 volts.

Example 16-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicAcid acetyl-amide Sodium Salt

[0261]6-[4-cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid amide (166.3 mg, 0.413 mMol), was dissolved in methylene chloride(10 ml) and stirred under nitrogen. Acetic anhydride (126.5 mg, 1.239mMol), triethylamine (49.3 mg, 0.49 mMol) and N,N-dimethylaminopyridine(25.2 mg, 0.5 mMol) were added into the methylene chloride solution, andstirred for 18 hours. The reaction mixture was washed with water andbrine, dried with magnesium sulfate, filtered, and evaporated. Theresidue was chromatographed on silica, eluting with 0.75%methanol/methylene chloride, to give a free acid in 80% yield. The freeacid was converted to the sodium salt by reacting the free acid with oneequivalent of sodium hydroxide in ethanol, evaporation, and drying underhigh vacuum. The desired product was isolated by chromatography onsilica gel column. MS: 443.5 ES, r.t.: 3.0 minutes.

Example 26-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicAcid propionyl-amide Sodium Salt

[0262]6-[4-cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid amide (166.3 mg, 0.413 mMol), was dissolved in methylene chloride(10 ml) and stirred under nitrogen. Propionic anhydride (161.24 mg,1.239 mMol), triethylamine (49.3 mg, 0.49 mMol) andN,N-dimethylaminopyridine (25.2 mg, 0.5 mMol) were added into themethylene chloride solution, and stirred for 18 hours. The reactionmixture was washed with water and brine, dried with magnesium sulfate,filtered, and evaporated. The residue was chromatographed on silica,eluting with 0.75% methanol/methylene chloride, to give a free acid in80% yield. The free acid was converted to the sodium salt by reactingthe free acid with one equivalent of sodium hydroxide in ethanol,evaporation, and drying under high vacuum. The desired product wasisolated by chromatography on silica gel column. MS: 457.6 ES, r.t.: 3.1min.

[0263] The following compounds summarized in the following Table 2 maybe prepared according to the procedure described in the above Examples 1and 2 by using appropriate starting materials. TABLE 2

Ex.# A m R¹ R² R⁴ R⁵ B-R³ 1 A2, wherein 2 —CN —CF₃ —NH—(C═O)—CH₃ H—N—CH₂—C(CH₃)₃ X is > CH 2 A2, wherein 2 —CN —CF₃ —NH—(C═O)—CH₂CH₃ H—N—CH₂—C(CH₃)₃ X is > CH 3 A2, wherein 2 —CN —CF₃ —NH—(C═O)—CH(CH₃)₂ —H—N—CH₂—C(CH₃)₃ X is > CH 4 A2, wherein 2 —CN —CF₃ —NH—(C═O)—CH(CH₃)₂ —H—N—CH₂—C(CH₃)₃ X is > CH 5 A2, wherein 2 —CN —CF₃ —NH—(C═O)—O—CH(CH₃)₂—H —N—CH₂—C(CH₃)₃ X is > CH 6 A2, wherein 2 —CN —CF₃—NH—(C═O)—CH(CH₃)—CH₂CH₃ —H —N—CH₂—C(CH₃)₃ X is > CH 7 A2, wherein 2 —CN—CF₃ —NH—(C═O)—CH₃ —H —O—CH₂-(cyclopentyl) X is > CH 8 A2, wherein 2 —CN—CF₃ —NH—(C═O)—CH₂CH₃ —H —O—CH₂-(cyclopentyl) X is > CH 9 A2, wherein 2—CN —CF₃ —NH—(C═O)—CH(CH₃)₂ —H —O—CH₂-(cyclopentyl) X is > CH 10 A2,wherein 2 —CN —CF₃ —NH—(C═O)—O—CH(CH₃)₂ —H —O—CH₂—C(CH₃)₃ X is > CH 11A2, wherein 2 —CN —CF₃ —NH—(C═O)—CH(CH₃)—CH₂CH₃ —H —O—CH₂—C(CH₃)₃ X is >CH 12 A2, wherein 2 —CN —CF₃ —NH—(C═O)—CH₃ —H —O—CH₂—C(CH₃)₃ X is > CH13 A2, wherein 2 —CN —CF₃ —NH—(C═O)—CH₂CH₃ —H —O-(3-(CH₃)-cyclohexyl) Xis > CH 14 A2, wherein 2 —CN —CF₃ —NH—(C═O)—CH(CH₃)₂ —H—O-(3-(CH₃)-cyclohexyl) X is > CH 15 A2, wherein 2 —CN —CF₃—NH—(C═O)—O—CH(CH₃)₂ —H —O-(3-(CH₃)-cyclohexyl) X is > CH 16 A2, wherein2 —CN —CF₃ —NH—(C═O)—CH₃ —H —SO₂—CH(CH₃)—CH₂CH₃ X is > CH 17 A2, wherein2 —CN —CF₃ —NH—(C═O)—CH(CH₃)—CH₂CH₃ —H —SO₂—CH(CH₃)—CH₂CH₃ X is > CH 18A2, wherein 2 —CN —CF₃ —NH—(C═O)—O—CH(CH₃)₂ —H —SO₂—CH(CH₃)—CH₂CH₃ Xis > CH 19 A2, wherein 2 —CN —CHF₂ —NH—(C═O)—CH₃ —H —SO₂—CH(CH₃)—CH₂CH₃X is > CH 20 A2, wherein 2 —CN —CHF₂ —NH—(C═O)—CH₂CH₃ —H—SO₂—CH(CH₃)—CH₂CH₃ X is > CH 21 A2, wherein 2 —CN —CHF₂—NH—(C═O)—CH(CH₃)₂ —H —SO₂—CH(CH₃)—CH₂CH₃ X is > CH 22 A2, wherein 2 —CN—CF₃ —N═CH—N(CH₃)₂ —H —O—CH₂-(cyclobutyl) X is > CH 23 A2, wherein 2 —CN—CF₃ —N—CH₂CH₃ —H —N—CH₂—C(CH₃)₃ X is > CH 24 A2, wherein 2 —CN —CF₃—N—CH₂-(cyclopropyl) —H —N—CH₂-(tetrahydrofuran-2-yl) X is > CH

[0264] While the invention has been described and illustrated withreference to certain particular embodiments thereof, those skilled inthe art will appreciate that various adaptations, changes,modifications, substitutions, deletions, or additions of procedures andprotocols may be made without departing from the spirit and scope of theinvention. It is intended, therefore, that the invention be defined bythe scope of the claims that follow and that such claims be interpretedas broadly as is reasonable.

We claim:
 1. A compound of the formula I:

or a pharmaceutically acceptable salt thereof; wherein the ring of theformula (R⁵)-A-(SO_(m)R⁴) is selected from the group consisting of

m is 0, 1 or 2; X is >CR⁵ or >N; R¹ is a radical selected from the groupconsisting of H, —NO₂, —CN, (C₁-C₆)alkyl, (C₁-C₆)alkyl-SO₂—,(C₆-C₁₀)aryl-SO₂—, H—(C═O)—, (C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclyl-(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂-NH—(C═O)—,[(C₆-C₁₀)aryl]-NH—(C═O)—, [(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—(C═O)—,HO—NH—(C═O)—, or (C₁-C₆)alkyl-O—NH—(C═O)—; R² is a radical selected fromthe group consisting of H, —NO₂, —CN, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)cycloalkyl, (C₆-C₁₀)aryl, (C₁-C₉)heteroaryl, (C₁-C₉)heterocyclyl,(C₁-C₆)alkyl-O—, (C₃-C₇)cycloalkyl-O—, (C₆-C₁₀)aryl-O—,(C₁-C₉)heteroaryl-O—, (C₁-C₉)heterocyclyl-O—, H—(C═O)—,(C₁-C₆)alkyl-(C═O)—, (C₃-C₇)cycloalkyl-(C═O)—, (C₆-C₁₀)aryl-(C═O)—,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclyl-(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, (C₃-C₇)cycloalkyl-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclyl-O—(C═O)—, (C₁-C₆)alkyl-(C═O)—O—,(C₃-C₇)cycloalkyl-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₇)cycloalkyl-(C═O)—NH—,(C₆-C₁₀)aryl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclyl-(C═O)—NH—, (C₁-C₆)alkyl-O—(C═O)—NH—,(C₁-C₆)alkyl-NH—, [(C₁-C₆)alkyl]₂-N—, (C₃-C₇)cycloalkyl-NH—,[(C₃-C₇)cycloalkyl]₂-N—, [(C₆-C₁₀)aryl]-NH—, [(C₆-C₁₀)aryl]₂-N—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—, [(C₁-C₉)heteroaryl]-NH—,[(C₁-C₉)heteroaryl]₂-N—, [(C₁-C₉)heterocyclyl]-NH—,[(C₁-C₉)heterocyclyl]₂-N—, H₂N—(C═O)—, HO—NH—(C═O)—,(C₁-C₆)alkyl-O—NH—(C═O)—, [(C₁-C₆)alkyl]-NH—(C═O)—,[(C₁-C₆)alkyl]₂-NH—(C═O)—, [(C₃-C₇)cycloalkyl]-NH—(C═O)—,[(C₃-C₇)cycloalkyl]₂-NH—(C═O)—, ((C₆-C₁₀)aryl]-NH—(C═O)—,[(C₆-C₁₀)aryl)₂—NH—(C═O)—, [(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—(C═O)—,[(C₁-C₉)heteroaryl]-NH—(C═O)—, [(C₁-C₉)heteroaryl]₂-NH—(C═O)—,[(C₁-C₉)heterocyclyl]-NH—(C═O)—, (C₁-C₆)alkyl-S—, and (C₁-C₆)alkyloptionally substituted by one —OH substituent or by one to four fluorosubstituents; B is —O—, —S—, —SO—, —SO₂— or R⁶—N—; R³ is a radicalselected from the group consisting of (C₁-C₆)alkyl, (C₆-C₁₀)aryl,(C₃-C₁₀)cycloalkyl, (C₁-C₉)heteroaryl and (C₁-C₉)heterocyclyl; whereineach of said R³ (C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl,(C₁-C₉)heteroaryl or (C₁-C₉)heterocyclyl radicals may optionally besubstituted with one to three substituents independently selected fromthe group consisting of halo, —NH₂, —OH, —CN, —NO₂, —OCF₃, —CF₃,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₆-C₁₀)aryl,(C₃-C₁₀)cycloalkyl, (C₁-C₉)heteroaryl, (C₁-C₉)heterocyclyl,(C₁-C₆)alkyl-O—, (C₃-C₁₀)cycloalkyl-O—, (C₆-C₁₀)aryl-O—,(C₁-C₉)heteroaryl-O—, and (C₁-C₉)heterocyclyl-O—; wherein each of saidR³ (C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, (C₁-C₉)heterocyclylor (C₁-C₉)heteroaryl substituents may optionally be substituted with oneto three moieties independently selected from the group consisting ofhalo, —NH₂, HO—, (C₁-C₆)alkyl-O—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, —CN, —NO₂, —OCF₃, and —CF₃; wherein each of said —NH₂substituents may optionally be substituted by one to two moietiesindependently selected from the group consisting of (C₁-C₆)alkyl,(C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, (C₁-C₉)heterocyclyl and(C₁-C₉)heteroaryl, wherein said moieties are optionally substituted byone or two sub-moieties independently selected from the group consistingof halo, —NH₂, HO—, (C₁-C₆)alkyl-O—, (C₁-C₆)alkyl, —OCF₃ and —CF₃; R⁴ isa radical selected from the group consisting of (C₁-C₆)alkyl-NH—,[(C₁-C₆)alkyl]₂-N—, (C₃-C₇)cycloalkyl-NH—, (C₆-C₁₀)aryl-NH—,(C₁-C₉)heteroaryl-NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₇)cycloalkyl-(C═O)—NH—, (C₆-C₁₀)aryl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₆)alkyl-O—(C═O)—NH—,(C₃-C₇)cycloalkyl-O—(C═O)—NH—, (C₆-C₁₀)aryl-O—(C═O)—NH—,(C₁-C₉)heteroaryl-O—(C═O)—NH—, (C₁-C₆)alkyl-NH—(C═O)—NH—,[(C₁-C₆)alkyl]₂-NH—(C═O)—NH—, (C₃-C₇)cycloalkyl-NH—(C═O)—NH—,(C₆-C₁₀)aryl-NH—(C═O)—NH—, (C₁-C₉)heteaoaryl]-NH—(C═O)—NH—,(C₁-C₆)alkyl-NH—HC═N—, [C₁-C₆)alkyl]₂N—HC═N—, and (C₆-C₁₀)aryl-NH—HC═N—;R⁵ is a radical selected from the group consisting of H, halo, —OH,(C₁-C₆)alkyl-O—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, —CN,H—(C═O)—, (C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkyl-(C═O)—O—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, (C₁-C₆)alkyl-NH—, [(C₁-C₆)alkyl]₂-N—,(C₃-C₇)cycloalkyl-NH—, (C₆-C₁₀)aryl-NH—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—, (C₁-C₉)heteroaryl-NH—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂-NH—(C═O)—, (C₆-C₁₀)aryl-(C═O)—,[(C₁-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]—(C═O)—,(C₁-C₆)alkyl-O—NH—(C═O)—,(C₁-C₅)alkyl-S—, and (C₁-C₆)alkyl optionally substituted with one tofour fluoro substituents; and R⁶ is a radical selected from the groupconsisting of H, (C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl,(C₁-C₉)heteroaryl and (C₁-C₉)heterocyclyl.
 2. The compound according toclaim 1 wherein R⁴ is a radical selected from the group consisting of(C₁-C₆)alkyl-NH— and (C₃-C₇)cycloalkyl-NH—.
 3. The compound according toclaim 1 wherein R⁴ is a radical selected from the group consisting of(C₁-C₆)alkyl-(C═O)—NH— and (C₆-C₁₀)aryl-(C═O)—NH—.
 4. The compoundaccording to claim 1 wherein R⁴ is a radical selected from the groupconsisting of (C₁-C₆)alkyl-O—(C═O)—NH— and (C₆-C₁₀)aryl-O—(C═O)—NH—. 5.The compound according to claim 1 wherein R⁴ is a radical selected fromthe group consisting of [(C₁-C₆)alkyl]-NH—(C═O)—NH—,[(C₁-C₆)alkyl]₂-NH—(C═O)—NH—, and [(C₆-C₁₀)aryl]-NH—(C═O)—NH—.
 6. Thecompound according to claim 1 wherein R⁴ is a radical selected from thegroup consisting of [(C₁-C₆)alkyl]-NH—HC═N—, [C₁-C₆)alkyl]₂N—HC═N—, and[(C₆-C₁₀)aryl]-NH—HC═N—.
 7. The compound according to claim 1 wherein R⁴is a radical selected from the group consisting of(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl-O—(C═O)—NH—, (C₁-C₆)alkyl-NH—, and[(C₁-C₆)alkyl]-NH—HC═N—.
 8. The compound according to claim 1 wherein Bis —O—.
 9. The compound according to claim 1 wherein B is —S—, —SO—, or—SO₂—.
 10. The compound according to claim 1 wherein B is R⁶—N—.
 11. Thecompound according to claim 1 wherein R³ is a radical selected from thegroup consisting of (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, and(C₁-C₉)heterocyclyl.
 12. The compound according to claim 1 wherein thering of the formula (R⁵)-A-(SO_(m)R⁴) is of the formula

wherein X is >CH and m is
 2. 13. The compound according to claim 1wherein the ring of the formula (R⁵)-A-(SO_(m)R⁴) is of the formula


14. The compound according to claim 1 wherein R¹ is a radical selectedfrom the group consisting of —NO₂, —CN, (C₁-C₆)alkyl, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, and[(C₁-C₆)alkyl]₂-NH—(C═O)—.
 14. The compound according to claim 1 whereinR² is a radical selected from the group consisting of H, —NO₂, —CN, and(C₁-C₆)alkyl optionally substituted by one —OH substituent or by one tofour fluoro substituents.
 15. A compound according to claim 1 whereinsaid compound is selected from the group consisting of:6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid acetyl-amide;6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid propionyl-amide;6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid isobutyryl-amide;6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid (2,2-dimethyl-propionyl)-amide;6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid (1,1-dimethyl)-ethoxy-amide;6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid (3-methyl-butyryl)-amide;6-(4-Cyano-5-cyclopentylmethoxy-3-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonicacid acetyl amide;6-(4-Cyano-5-cyclopentylmethoxy-3-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonicacid propionyl amide; 6-(4-Cyano-5-cyclopentylmethoxy-3-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonic acidisobutyryl amide;6-[4-Cyano-5-(2,2-dimethyl-propoxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid (1,1-dimethylethoxy)amide;6-[4-Cyano-5-(2,2-dimethyl-propoxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid (3-methyl-butyryl) amide;6-[4-Cyano-5-(2,2-dimethyl-propoxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid acetyl amide;6-[4-Cyano-5-(3-methyl-cyclohexyloxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid propionyl amide;6-[4-Cyano-5-(3-methyl-cyclohexyloxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid isobutyryl amide;6-[4-Cyano-5-(3-methyl-cyclohexyloxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonicacid (1,1-dimethylethoxy) amide;6-(5-sec-Butylsulfanyl-4-cyano-3-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonic acid acetyl amide;6-(5-sec-Butylsulfanyl-4-cyano-3-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonic acid (3-methyl-butyryl)amide;6-(5-sec-Butylsulfanyl-4-cyano-3-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonicacid (1,1-dimethylethoxy)amide;6-(5-sec-Butylsulfanyl-4-cyano-3-difluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonicacid acetyl amide;6-(5-sec-Butylsulfanyl-4-cyano-3-difluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonic acid propionyl amide; and6-(5-sec-Butylsulfanyl-4-cyano-3-difluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonicacid isobutyryl amide; or a pharmaceutically acceptable salt thereof.16. A pharmaceutical composition for the treatment of a conditionselected from the group consisting of arthritis, fever, common cold,dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn'sdisease, emphysema, acute respiratory distress syndrome, asthma,bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease,organ transplant toxicity, cachexia, allergic reactions, allergiccontact hypersensitivity, cancer, tissue ulceration, peptic ulcers,gastritis, regional enteritis, ulcerative colitis, diverticulitis,recurrent gastrointestinal lesion, gastrointestinal bleeding,coagulation, anemia, synovitis, gout, ankylosing spondylitis,restenosis, periodontal disease, epidermolysis bullosa, osteoporosis,loosening of artificial joint implants, atherosclerosis, aorticaneurysm, periarteritis nodosa, congestive heart failure, myocardialinfarction, stroke, cerebral ischemia, head trauma, spinal cord injury,neuralgia, neuro-degenerative disorders, autoimmune disorders,Huntington's disease, Parkinson's disease, migraine, depression,peripheral neuropathy, pain, gingivitis, cerebral amyloid angiopathy,nootropic or cognition enhancement, amyotrophic lateral sclerosis,multiple sclerosis, ocular angiogenesis, corneal injury, maculardegeneration, conjunctivitis, abnormal wound healing, muscle or jointsprains or strains, tendonitis, skin disorders, myasthenia gravis,polymyositis, myositis, bursitis, burns, diabetes, tumor invasion, tumorgrowth, tumor metastasis, corneal scarring, scleritis, immunodeficiencydiseases, sepsis, premature labor, hypoprothrombinemia, hemophilia,thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, kidneydisease, Rickettsial infections, Protozoan diseases, reproductivedisorders and septic shock in a mammal, comprising an amount of acompound of claim 1 or a pharmaceutically acceptable salt thereofeffective in such treatments and a pharmaceutically acceptable carrier.17. A pharmaceutical composition for the treatment of a disorder orcondition that can be treated by selectively inhibiting COX-2 in amammal, comprising a COX-2 selective inhibiting effective amount of acompound according to claim 1 or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.
 18. A method fortreating a condition selected from the group consisting of arthritis,fever, common cold, dysmenorrhea, menstrual cramps, inflammatory boweldisease, Crohn's disease, emphysema, acute respiratory distresssyndrome, asthma, bronchitis, chronic obstructive pulmonary disease,Alzheimer's disease, organ transplant toxicity, cachexia, allergicreactions, allergic contact hypersensitivity, cancer, tissue ulceration,peptic ulcers, gastritis, regional enteritis, ulcerative colitis,diverticulitis, recurrent gastrointestinal lesion, gastrointestinalbleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis,restenosis, periodontal disease, epidermolysis bullosa, osteoporosis,loosening of artificial joint implants, atherosclerosis, aorticaneurysm, periarteritis nodosa, congestive heart failure, myocardialinfarction, stroke, cerebral ischemia, head trauma, spinal cord injury,neuralgia, neuro-degenerative disorders, autoimmune disorders,Huntington's disease, Parkinson's disease, migraine, depression,peripheral neuropathy, pain, gingivitis, cerebral amyloid angiopathy,nootropic or cognition enhancement, amyotrophic lateral sclerosis,multiple sclerosis, ocular angiogenesis, corneal injury, maculardegeneration, conjunctivitis, abnormal wound healing, muscle or jointsprains or strains, tendonitis, skin disorders, myasthenia gravis,polymyositis, myositis, bursitis, burns, diabetes, tumor invasion, tumorgrowth, tumor metastasis, corneal scarring, scleritis, immunodeficiencydiseases, sepsis, premature labor, hypoprothrombinemia, hemophilia,thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, kidneydisease, Rickettsial infections, Protozoan diseases, reproductivedisorders, and septic shock in a mammal, comprising administering tosaid mammal an amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof effective in treating such acondition.
 19. A method for treating a disorder or condition that can betreated by selectively inhibiting COX-2 in a mammal, comprisingadministering to a mammal requiring such treatment a COX-2 selectiveinhibiting effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.